anti-serum albumin binding variants

ABSTRACT

The invention relates to improved variants of the anti-serum albumin immunoglobulin single variable domain DOM7h-11, as well as ligands and drug conjugates comprising such variants, compositions, nucleic acids, vectors and hosts.

The invention relates to improved variants of the anti-serum albuminimmunoglobulin single variable domain DOM7h-11, as well as ligands anddrug conjugates comprising such variants, compositions, nucleic acids,vectors and hosts.

BACKGROUND OF THE INVENTION

WO04003019 and WO2008/096158 disclose anti-serum albumin (SA) bindingmoieties, such as anti-SA immunoglobulin single variable domains (dAbs),which have therapeutically-useful half-lives. These documents disclosemonomer anti-SA dAbs as well as multi-specific ligands comprising suchdAbs, eg, ligands comprising an anti-SA dAb and a dAb that specificallybinds a target antigen, such as TNFR1. Binding moieties are disclosedthat specifically bind serum albumins from more than one species, eghuman/mouse cross-reactive anti-SA dAbs.

WO05118642 and WO2006/059106 disclose the concept of conjugating orassociating an anti-SA binding moiety, such as an anti-SA immunoglobulinsingle variable domain, to a drug, in order to increase the half-life ofthe drug. Protein, peptide and NCE (new chemical entity) drugs aredisclosed and exemplified. WO2006/059106 discloses the use of thisconcept to increase the half-life of insulintropic agents, eg, incretinhormones such as glucagon-like peptide (GLP)-1.

Reference is also made to Holt et al, “Anti-Serum albumin domainantibodies for extending the half-lives of short lived drugs”, ProteinEngineering, Design & Selection, vol 21, no 5, pp 283-288, 2008.

WO2008/096158 discloses DOM7h-11, which is a good anti-SA dAb. It wouldbe desirable to provide improved dAbs that are variants of DOM7h-11 andthat specifically bind serum albumin, preferably albumins from human andnon-human species, which would provide utility in animal models ofdisease as well as for human therapy and/or diagnosis. It would also bedesirable to provide for the choice between relatively modest- andhigh-affinity anti-SA binding moieties (dAbs). Such moieties could belinked to drugs, the anti-SA binding moiety being chosen according tothe contemplated end-application. This would allow the drug to be bettertailored to treating and/or preventing chronic or acute indications,depending upon the choice of anti-SA binding moiety. It would also bedesirable to provide anti-dAbs, that are monomeric or substantially soin solution. This would especially be advantageous when the anti-SA dAbis linked to a binding moiety, eg, a dAb, that specifically binds acell-surface receptor, such as TNFR1, with the aim of antagonizing thereceptor. The monomeric state of the anti-SA dAb is useful in reducingthe chance of receptor cross-linking, since multimers are less likely toform which could bind and cross-link receptors (eg, TNFR1) on the cellsurface, thus increasing the likelihood of receptor agonism anddetrimental receptor signaling.

SUMMARY OF THE INVENTION

Aspects of the present invention solve these problems.

To this end, the present inventors surprisingly found that beneficialmutations can be targeted to the FW2/CDR2 junction (positions 49 to 51,numbering according to Kabat) of DOM7h-11.

In one aspect the invention, therefore, provides an anti-serum albumin(SA) immunoglobulin single variable domain variant of DOM7h-11, whereinthe variant comprises at least one mutation in the FW2/CDR2 junction(positions 49 to 51, numbering according to Kabat) compared to DOM7h-11,and wherein the variant has from 2 to 8 changes compared to the aminoacid sequence of DOM7h-11.

In one aspect the invention provides an anti-serum albumin (SA)immunoglobulin single variable domain variant of DOM7h-11, wherein thevariant comprises a Met at position 32 (numbering according to Kabat)compared to DOM7h-11, and wherein the variant has from 0 to 4 furtherchanges compared to the amino acid sequence of DOM7h-11.

Embodiments of either aspect of the invention provide DOM7h-11 variantsof good anti-serum albumin affinities. The choice of variant can allowfor tailoring of half-life according to the desired therapeutic and/orprophylactic setting. For example, in one embodiment, the affinity ofthe variant for serum albumin is relatively high, such that the variantwould be useful for inclusion in products that find utility in treatingand/or preventing chronic or persistent diseases, conditions, toxicityor other chronic indications. In one embodiment, the affinity of thevariant for serum albumin is relatively modest, such that the variantwould be useful for inclusion in products that find utility in treatingand/or preventing acute diseases, conditions, toxicity or other acuteindications. In one embodiment, the affinity of the variant for serumalbumin is intermediate, such that the variant would be useful forinclusion in products that find utility in treating and/or preventingacute or chronic diseases, conditions, toxicity or other acute orchronic indications.

It is conceivable that a molecule with an appropriately high affinityand specificity for serum albumin would stay in circulation long enoughto have the desired therapeutic effect (Tomlinson, Nature Biotechnology22, 521-522 (2004)). Here, a high affinity anti-SA variant would stay inserum circulation matching that of the species' serum albumin(WO2008096158). Once in circulation, any fused therapeutic agent to theAlbudAb™ variant (an AlbudAb is an anti-serum albumin dAb orimmunoglobulin single variable domain), be it NCE, peptide or protein,consequently would be able to act longer on its target and exhibit alonger lasting therapeutic effect. This would allow for targetingchronic or persistent diseases without the need of frequent dosing.

A variant with moderate affinity (but specificity to SA) would only stayin serum circulation for a short time (eg, for a few hours or a fewdays) allowing for the specific targeting of therapeutic targetsinvolved in acute diseases by the fused therapeutic agent.

This way it is possible to tailor the anti-SA-containing product to thetherapeutic disease area by choosing an anti-SA variant with theappropriate albumin binding affinity and/or serum half-life.

An aspect of the invention provides a multispecific ligand comprisingany anti-SA variant as described above and a binding moiety thatspecifically binds a target antigen other than SA.

An aspect of the invention provides a fusion product, eg, a fusionprotein or fusion with a peptide or NCE (new chemical entity) drug,comprising a polypeptide, protein, peptide or NCE drug fused orconjugated (for an NCE) to any variant as described above, wherein thevariant is DOM7h-11-15 or DOM7h-11-15^(S12P) (or a variant having anamino acid that is at least 95, 96, 97, 98 or 99% identical to the aminoacid sequence of DOM7h-11-15) or DOM7h-11-12 (or a variant having anamino acid that is at least 95, 96, 97, 98 or 99% identical to the aminoacid sequence of DOM7h-11-12). DOM7h-11-15 and DOM7h-11-12 give only amodest drop in affinity when fused or conjugated to partner making themuseful in fusion products. DOM7h-11-15^(S12P) is identical toDOM7h-11-15, with the exception that position 12 (numbering according toKabat) is a proline instead of a serine. This provides advantages setout in WO08052933, including to reduce binding to Protein-L of fusionproteins containing this domain antibody and to facilitate purification.The entire disclosure of WO08052933 is incorporated herein by reference.Similarly, the invention provides a DOM7h-11 variant as disclosed hereinwherein the variant comprises an amino acid sequence as set out belowwith the exception that position 12 (numbering according to Kabat) is aproline. The invention also provides fusion proteins, conjugates orcomposition comprising such DOM7h-11 variants.

One aspect of the invention provides a variant of DOM7h-11 thatcomprises an amino acid sequence that is identical to the amino acidsequence of DOM7h-11-15^(S12P) or has up to 4 changes compared to theamino acid sequence of DOM7h-11-15^(S12P), provided that the amino acidsequence of the variant has at least one mutation in the FW2/CDR2junction (positions 49 to 51, numbering according to Kabat).

An aspect of the invention provides a composition comprising a variant,fusion protein or ligand of any preceding aspect and a pharmaceuticallyacceptable diluent, carrier, excipient or vehicle.

An aspect of the invention provides a method of treating or preventing adisease or disorder in a patient, comprising administering at least onedose of a variant according to any aspect or embodiment of the inventionto said patient.

An aspect of the invention provides a polypeptide fusion or conjugatecomprising an anti-serum albumin dAb as disclosed herein (eg,DOM7h-11-15 or DOM7h-11-3 or DOM7h-11-15^(S12P) or DOM7h-11-15^(S12P)with up to 4 changes compared to the amino acid sequence ofDOM7h-11-15^(S12P)) and an incretin or insulinotropic agent, eg,exendin-4, GLP-1 (7-37), GLP-1 (6-36) or any incretin or insulinotropicagent disclosed in WO06/059106, these agents being explicitlyincorporated herein by reference as though written herein for inclusionin the present invention and claims below.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1: Amino-acid sequence alignment for DOM7h-11 variant dAbs. A “.”at a particular position indicates the same amino as found in DOM7h-11at that position. The CDRs are indicated by underlining and bold text(the first underlined sequence is CDR1, the second underlined sequenceis CDR2 and the third underlined sequence is CDR3).

FIG. 2: Kinetic parameters of DOM7h-11 variants. KD units=nM; Kdunits=sec⁻¹; Ka units=M⁻¹ sec⁻¹. The notation A e-B means A×10^(−B) andC e D means C×10^(D). The overall kinetic ranges in various species, assupported by the examples below, are indicated. Optional ranges are alsoprovided for use in particular therapeutic settings (acute or chronicindications, conditions or diseases and “intermediate” for use in bothchronic and acute settings). High affinity dAbs and products comprisingthese are useful for chronic settings. Medium affinity dAbs and productscomprising these are useful for intermediate settings. Low affinity dAbsand products comprising these are useful for acute settings. Theaffinity in this respect is the affinity for serum albumin. Variousexample anti-serum dAbs and fusion proteins are listed, and thesesupport the ranges disclosed. Many of the examples have favourablekinetics in human and one or more non-human animals (eg, in human andCynomolgus monkey and/or mouse). Choice of dAb or product comprisingthis can be tailored, according to the invention, depending on thesetting (eg, chronic or acute) to be treated therapeutically.

DETAILED DESCRIPTION OF THE INVENTION

Within this specification the invention has been described, withreference to embodiments, in a way which enables a clear and concisespecification to be written. It is intended and should be appreciatedthat embodiments may be variously combined or separated without partingfrom the invention.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art (e.g., in cell culture, molecular genetics, nucleic acidchemistry, hybridization techniques and biochemistry). Standardtechniques are used for molecular, genetic and biochemical methods (seegenerally, Sambrook et al., Molecular Cloning: A Laboratory Manual, 2ded. (1989) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y.and Ausubel et al., Short Protocols in Molecular Biology (1999) 4^(th)Ed, John Wiley & Sons, Inc. which are incorporated herein by reference)and chemical methods.

As used herein, the term “antagonist of Tumor Necrosis Factor Receptor 1(TNFR1)” or “anti-TNFR1 antagonist” or the like refers to an agent(e.g., a molecule, a compound) which binds TNFR1 and can inhibit a(i.e., one or more) function of TNFR1. For example, an antagonist ofTNFR1 can inhibit the binding of TNFα to TNFR1 and/or inhibit signaltransduction mediated through TNFR1. Accordingly, TNFR1-mediatedprocesses and cellular responses (e.g., TNFα-induced cell death in astandard L929 cytotoxicity assay) can be inhibited with an antagonist ofTNFR1.

A “patient” is any animal, eg, a mammal, eg, a non-human primate (suchas a baboon, rhesus monkey or Cynomolgus monkey), mouse, human, rabbit,rat, dog, cat or pig. In one embodiment, the patient is a human.

As used herein, “peptide” refers to about two to about 50 amino acidsthat are joined together via peptide bonds.

As used herein, “polypeptide” refers to at least about 50 amino acidsthat are joined together by peptide bonds. Polypeptides generallycomprise tertiary structure and fold into functional domains.

As used herein an antibody refers to IgG, IgM, IgA, IgD or IgE or afragment (such as a Fab, F(ab′)₂, Fv, disulphide linked Fv, scFv, closedconformation multispecific antibody, disulphide-linked scFv, diabody)whether derived from any species naturally producing an antibody, orcreated by recombinant DNA technology; whether isolated from serum,B-cells, hybridomas, transfectomas, yeast or bacteria.

As used herein, “antibody format” refers to any suitable polypeptidestructure in which one or more antibody variable domains can beincorporated so as to confer binding specificity for antigen on thestructure. A variety of suitable antibody formats are known in the art,such as, chimeric antibodies, humanized antibodies, human antibodies,single chain antibodies, bispecific antibodies, antibody heavy chains,antibody light chains, homodimers and heterodimers of antibody heavychains and/or light chains, antigen-binding fragments of any of theforegoing (e.g., a Fv fragment (e.g., single chain Fv (scFv), adisulfide bonded Fv), a Fab fragment, a Fab′ fragment, a F(ab′)₂fragment), a single antibody variable domain (e.g., a dAb, V_(H),V_(HH), V_(L)), and modified versions of any of the foregoing (e.g.,modified by the covalent attachment of polyethylene glycol or othersuitable polymer or a humanized V_(HH)).

The phrase “immunoglobulin single variable domain” refers to an antibodyvariable domain (V_(H), V_(HH), V_(L)) that specifically binds anantigen or epitope independently of different V regions or domains. Animmunoglobulin single variable domain can be present in a format (e.g.,homo- or hetero-multimer) with other variable regions or variabledomains where the other regions or domains are not required for antigenbinding by the single immunoglobulin variable domain (i.e., where theimmunoglobulin single variable domain binds antigen independently of theadditional variable domains). A “domain antibody” or “dAb” is the sameas an “immunoglobulin single variable domain” as the term is usedherein. A “single immunoglobulin variable domain” is the same as an“immunoglobulin single variable domain” as the term is used herein. A“single antibody variable domain” or an “antibody single variabledomain” is the same as an “immunoglobulin single variable domain” as theterm is used herein. An immunoglobulin single variable domain is in oneembodiment a human antibody variable domain, but also includes singleantibody variable domains from other species such as rodent (forexample, as disclosed in WO 00/29004, the contents of which areincorporated herein by reference in their entirety), nurse shark andCamelid V_(HH) dAbs. Camelid V_(HH) are immunoglobulin single variabledomain polypeptides that are derived from species including camel,llama, alpaca, dromedary, and guanaco, which produce heavy chainantibodies naturally devoid of light chains. The V_(HH) may behumanized.

A “domain” is a folded protein structure which has tertiary structureindependent of the rest of the protein. Generally, domains areresponsible for discrete functional properties of proteins, and in manycases may be added, removed or transferred to other proteins withoutloss of function of the remainder of the protein and/or of the domain. A“single antibody variable domain” is a folded polypeptide domaincomprising sequences characteristic of antibody variable domains. Ittherefore includes complete antibody variable domains and modifiedvariable domains, for example, in which one or more loops have beenreplaced by sequences which are not characteristic of antibody variabledomains, or antibody variable domains which have been truncated orcomprise N- or C-terminal extensions, as well as folded fragments ofvariable domains which retain at least the binding activity andspecificity of the full-length domain.

In the instant application, the term “prevention” and “preventing”involves administration of the protective composition prior to theinduction of the disease or condition. “Treatment” and “treating”involves administration of the protective composition after disease orcondition symptoms become manifest. “Suppression” or “suppressing”refers to administration of the composition after an inductive event,but prior to the clinical appearance of the disease or condition.

As used herein, the term “dose” refers to the quantity of ligandadministered to a subject all at one time (unit dose), or in two or moreadministrations over a defined time interval. For example, dose canrefer to the quantity of ligand (e.g., ligand comprising animmunoglobulin single variable domain that binds target antigen)administered to a subject over the course of one day (24 hours) (dailydose), two days, one week, two weeks, three weeks or one or more months(e.g., by a single administration, or by two or more administrations).The interval between doses can be any desired amount of time. The term“pharmaceutically effective” when referring to a dose means sufficientamount of the ligand, domain or pharmaceutically active agent to providethe desired effect. The amount that is “effective” will vary fromsubject to subject, depending on the age and general condition of theindividual, the particular drug or pharmaceutically active agent and thelike. Thus, it is not always possible to specify an exact “effective”amount applicable for all patients. However, an appropriate “effective”dose in any individual case may be determined by one of ordinary skillin the art using routine experimentation.

Methods for pharmacokinetic analysis and determination of ligand (eg,single variable domain, fusion protein or multi-specific ligand)half-life will be familiar to those skilled in the art. Details may befound in Kenneth, A et al: Chemical Stability of Pharmaceuticals: AHandbook for Pharmacists and in Peters et al, Pharmacokinetc analysis: APractical Approach (1996). Reference is also made to “Pharmacokinetics”,M Gibaldi & D Perron, published by Marcel Dekker, 2^(nd) Rev. ex edition(1982), which describes pharmacokinetic parameters such as t alpha and tbeta half lives and area under the curve (AUC). Optionally, allpharmacokinetic parameters and values quoted herein are to be read asbeing values in a human. Optionally, all pharmacokinetic parameters andvalues quoted herein are to be read as being values in a mouse or rat orCynomolgus monkey.

Half lives (t½ alpha and t½ beta) and AUC can be determined from a curveof serum concentration of ligand against time. The WinNonlin analysispackage, eg version 5.1 (available from Pharsight Corp., Mountain View,Calif. 94040, USA) can be used, for example, to model the curve. Whentwo-compartment modeling is used, in a first phase (the alpha phase) theligand is undergoing mainly distribution in the patient, with someelimination. A second phase (beta phase) is the phase when the ligandhas been distributed and the serum concentration is decreasing as theligand is cleared from the patient. The t alpha half life is the halflife of the first phase and the t beta half life is the half life of thesecond phase. Thus, in one embodiment, in the context of the presentinvention, the variable domain, fusion protein or ligand has a tαhalf-life in the range of (or of about) 15 minutes or more. In oneembodiment, the lower end of the range is (or is about) 30 minutes, 45minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours,10 hours, 11 hours or 12 hours. In addition, or alternatively, thevariable domain, fusion protein or ligand according to the inventionwill have a tα half life in the range of up to and including 12 hours(or about 12 hours). In one embodiment, the upper end of the range is(or is about) 11, 10, 9, 8, 7, 6 or 5 hours. An example of a suitablerange is (or is about) 1 to 6 hours, 2 to 5 hours or 3 to 4 hours.

In one embodiment, the present invention provides the variable domain,fusion protein or ligand according to the invention has a tβ half-lifein the range of (or of about) 2.5 hours or more. In one embodiment, thelower end of the range is (or is about) 3 hours, 4 hours, 5 hours, 6hours, 7 hours, 10 hours, 11 hours, or 12 hours. In addition, oralternatively, the tβ half-life is (or is about) up to and including 21or 25 days. In one embodiment, the upper end of the range is (or isabout) 12 hours, 24 hours, 2 days, 3 days, 5 days, 10 days, 15 days, 19days, 20 days, 21 days or 22 days. For example, the variable domain,fusion protein or ligand according to the invention will have a tβ halflife in the range 12 to 60 hours (or about 12 to 60 hours). In a furtherembodiment, it will be in the range 12 to 48 hours (or about 12 to 48hours). In a further embodiment still, it will be in the range 12 to 26hours (or about 12 to 26 hours).

As an alternative to using two-compartment modeling, the skilled personwill be familiar with the use of non-compartmental modeling, which canbe used to determine terminal half-lives (in this respect, the term“terminal half-life” as used herein means a terminal half-lifedetermined using non-compartmental modeling). The WinNonlin analysispackage, eg version 5.1 (available from Pharsight Corp., Mountain View,Calif. 94040, USA) can be used, for example, to model the curve in thisway. In this instance, in one embodiment the single variable domain,fusion protein or ligand has a terminal half life of at least (or atleast about) 8 hours, 10 hours, 12 hours, 15 hours, 28 hours, 20 hours,1 day, 2 days, 3 days, 7 days, 14 days, 15 days, 16 days, 17 days, 18days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days or 25 days.In one embodiment, the upper end of this range is (or is about) 24hours, 48 hours, 60 hours or 72 hours or 120 hours. For example, theterminal half-life is (or is about) from 8 hours to 60 hours, or 8 hoursto 48 hours or 12 to 120 hours, eg, in man.

In addition, or alternatively to the above criteria, the variabledomain, fusion protein or ligand according to the invention has an AUCvalue (area under the curve) in the range of (or of about) 1 mg.min/mlor more. In one embodiment, the lower end of the range is (or is about)5, 10, 15, 20, 30, 100, 200 or 300 mg.min/ml. In addition, oralternatively, the variable domain, fusion protein or ligand accordingto the invention has an AUC in the range of (or of about) up to 600mg.min/ml. In one embodiment, the upper end of the range is (or isabout) 500, 400, 300, 200, 150, 100, 75 or 50 mg.min/ml. Advantageouslythe variable domain, fusion protein or ligand will have an AUC in (orabout in) the range selected from the group consisting of the following:15 to 150 mg.min/ml, 15 to 100 mg.min/ml, 15 to 75 mg.min/ml, and 15 to50 mg.min/ml.

“Surface Plasmon Resonance”: Competition assays can be used to determineif a specific antigen or epitope, such as human serum albumin, competeswith another antigen or epitope, such as cynomolgus serum albumin, forbinding to a serum albumin binding ligand described herein, such as aspecific dAb. Similarly competition assays can be used to determine if afirst ligand such as dAb, competes with a second ligand such as a dAbfor binding to a target antigen or epitope. The term “competes” as usedherein refers to substance, such as a molecule, compound, preferably aprotein, which is able to interfere to any extent with the specificbinding interaction between two or more molecules. The phrase “does notcompetitively inhibit” means that substance, such as a molecule,compound, preferably a protein, does not interfere to any measurable orsignificant extent with the specific binding interaction between two ormore molecules. The specific binding interaction between two or moremolecules preferably includes the specific binding interaction between asingle variable domain and its cognate partner or target. Theinterfering or competing molecule can be another single variable domainor it can be a molecule that is structurally and/or functionally similarto a cognate partner or target.

The term “binding moiety” refers to a domain that specifically binds anantigen or epitope independently of a different epitope or antigenbinding domain. A binding moiety may be a domain antibody (dAb) or maybe a domain which is a derivative of a non-immunoglobulin proteinscaffold, eg, a scaffold selected from the group consisting of CTLA-4,lipocalin, SpA, an adnectin, affibody, an avimer, GroEl, transferrin,GroES and fibronectin, which binds to a ligand other than the naturalligand (in the case of the present invention, the moiety binds serumalbumin). See WO2008/096158, which discloses examples of proteinscaffolds and methods for selecting antigen or epitope-specific bindingdomains from repertoires (see Examples 17 to 25). These specificdisclosures of WO2008/096158 are expressly incorporated herein byreference as though explicitly written herein and for use with thepresent invention, and it is contemplated that any part of suchdisclosure can be incorporated into one or more claims herein).

In one aspect, the invention provides an anti-serum albumin (SA)immunoglobulin single variable domain variant of DOM7h-11, wherein thevariant comprises at least one mutation in the FW2/CDR2 junction(positions 49 to 51, numbering according to Kabat) compared to DOM7h-11,and wherein the variant has from 2 to 8 changes compared to the aminoacid sequence of DOM7h-11. Optionally, position 49 (according to Kabat)is Leu. Additionally or alternatively, position 50 (according to Kabat)is optionally Ala or Trp. Additionally or alternatively, position 51(according to Kabat) is optionally Phe or Asn. In one embodiment, thevariant comprises a mutation at each of positions 49, 50 and 51(numbering according to Kabat) compared to DOM7h-11. In one embodiment,the variant comprises a LFG motif, where L is at position 49 (numberingaccording to Kabat), wherein L, F and G are Leu, Phe and Glyrespectively.

In one embodiment, the variant comprises an amino acid sequence that isidentical to the amino acid sequence of a single variable domainselected from DOM7h-11-3, DOM7h-11-15, DOM7h-11-12 and DOM7h-11-19 orhas up to 4 changes compared to the selected amino acid sequence,provided that the amino acid sequence of the variant has at least onemutation in the FW2/CDR2 junction as defined above. In one embodiment,the variant comprises an amino acid sequence that is identical to theamino acid sequence of DOM7h-11-15^(S12P) or has up to 4 changescompared to the amino acid sequence of DOM7h-11-15^(S12P), provided thatthe amino acid sequence of the variant has at least one mutation in theFW2/CDR2 junction (positions 49 to 51, numbering according to Kabat). Inone embodiment, the variant comprises an amino acid sequence that isidentical to the amino acid sequence of a single variable domainselected from DOM7h-11-3, or has up to 4 changes compared to theselected amino acid sequence, provided that the amino acid sequence ofthe variant has L at position 49, W at position 50 and N at position 51.In one embodiment, the variant comprises an amino acid sequence that isidentical to the amino acid sequence of a single variable domainselected from DOM7h-11-12, or has up to 4 changes compared to theselected amino acid sequence, provided that the amino acid sequence ofthe variant has M at position 32 and L at position 49. In oneembodiment, the variant comprises an amino acid sequence that isidentical to the amino acid sequence of a single variable domainselected from DOM7h-11-15 or DOM7h-11-15^(S12P), or has up to 4 changescompared to the selected amino acid sequence, provided that the aminoacid sequence of the variant has M at position 32, L at position 49, Aat position 50 and F at position 51. In one embodiment, the variantcomprises an amino acid sequence that is identical to the amino acidsequence of a single variable domain selected from DOM7h-11-18, or hasup to 4 changes compared to the selected amino acid sequence, providedthat the amino acid sequence of the variant has M at position 32 and Hat position 87. In one embodiment, the variant comprises an amino acidsequence that is identical to the amino acid sequence of a singlevariable domain selected from DOM7h-11-19, or has up to 4 changescompared to the selected amino acid sequence, provided that the aminoacid sequence of the variant has M at position 32, L at position 49 andT at position 91. All numbering in this paragraph is according to Kabat.

An aspect of the invention provides an anti-serum albumin (SA)immunoglobulin single variable domain variant of DOM7h-11, wherein thevariant comprises a Met at position 32 (numbering according to Kabat)compared to DOM7h-11, and wherein the variant has from 0 to 4 furtherchanges compared to the amino acid sequence of DOM7h-11. Optionally, thevariant comprises at least one mutation in the FW2/CDR2 junction(positions 49 to 51, numbering according to Kabat) compared to DOM7h-11.

In one embodiment of any aspect of the invention, the variant comprisesat least one mutation compared to DOM7h-11 selected from the following

Position 49=L, Position 50=A or W, Position 51=For N, Position 87=H, andPosition 91=T.

In one embodiment, the variant comprises an amino acid sequence that isidentical to the amino acid sequence of a single variable domainselected from DOM7h-11-12, DOM7h-11-15, DOM7h-11-15^(S12P), DOM7h-11-18and DOM7h-11-19 or has up to 4 changes compared to the selected aminoacid sequence, provided that the amino acid sequence of the variant hasMet at position 32.

In one embodiment, the variant comprises one or more of the followingkinetic characteristics:—

-   -   (a) The variant comprises a binding site that specifically binds        human SA with a dissociation constant (KD) from (or from about)        0.1 to (or to about) 10000 nM, optionally from (or from about) 1        to (or to about) 6000 nM, as determined by surface plasmon        resonance;    -   (b) The variant comprises a binding site that specifically binds        human SA with an off-rate constant (K_(d)) from (or from about)        1.5×10⁻⁴ to (or to about) 0.1 sec⁻¹, optionally from (or from        about) 3×10⁻⁴ to (or to about) 0.1 sec⁻¹ as determined by        surface plasmon resonance;    -   (c) The variant comprises a binding site that specifically binds        human SA with an on-rate constant (K_(a)) from (or from about)        2×10⁶ to (or to about) 1×10⁴M⁻¹sec⁻¹, optionally from (or from        about) 1×10⁶ to (or to about) 2×10⁴ M⁻¹sec⁻¹ as determined by        surface plasmon resonance;    -   (d) The variant comprises a binding site that specifically binds        Cynomolgus monkey SA with a dissociation constant (KD) from (or        from about) 0.1 to (or to about) 10000 nM, optionally from (or        from about) 0.1 to (or to about) 6000 nM, as determined by        surface plasmon resonance;    -   (e) The variant of any preceding claim, wherein the variant        comprises a binding site that specifically binds Cynomolgus        monkey SA with an off-rate constant (K_(d)) from (or from about)        1.5×10⁻⁴ to (or to about) 0.1 sec⁻¹, optionally from (or from        about) 3×10⁻⁴ to (or to about) 0.1 sec⁻¹ as determined by        surface plasmon resonance;    -   (f) The variant of any preceding claim, wherein the variant        comprises a binding site that specifically binds Cynomolgus        monkey SA with an on-rate constant (K_(a)) from (or from about)        2×10⁶ to (or to about) 1×10⁴M⁻¹sec⁻¹, optionally from (or from        about) 1×10⁶ to (or to about) 5×10³M⁻¹sec⁻¹ as determined by        surface plasmon resonance;    -   (g) The variant comprises a binding site that specifically binds        rat SA with a dissociation constant (KD) from (or from about) 1        to (or to about) 10000 nM, optionally from (or from about) 20 to        (or to about) 6000 nM, as determined by surface plasmon        resonance;    -   (h) The variant comprises a binding site that specifically binds        rat SA with an off-rate constant (K_(J)) from (or from about)        2×10⁻³ to (or to about) 0.15 sec⁻¹, optionally from (or from        about) 9×10⁻³ to (or to about) 0.14 sec⁻¹ as determined by        surface plasmon resonance;    -   (i) The variant comprises a binding site that specifically binds        rat SA with an on-rate constant (K_(a)) from (or from about)        2×10⁶ to (or to about) 1×10⁴M⁻¹sec⁻¹, optionally from (or from        about) 1×10⁶ to (or to about) 3×10⁴M⁻¹sec⁻¹ as determined by        surface plasmon resonance;    -   (j) The variant comprises a binding site that specifically binds        mouse SA with a dissociation constant (KD) from (or from about)        1 to (or to about) 10000 nM as determined by surface plasmon        resonance;    -   (k) The variant comprises a binding site that specifically binds        mouse SA with an off-rate constant (K₁) from (or from about)        2×10⁻³ to (or to about) 0.15 sec⁻¹ as determined by surface        plasmon resonance; and/or    -   (l) The variant comprises a binding site that specifically binds        mouse SA with an on-rate constant (K_(a)) from (or from about)        2×10⁶ to (or to about) 1×10⁴M⁻¹sec⁻¹, optionally from (or from        about) 2×10⁶ to (or to about) 1.5×10⁴ M⁻¹sec⁻¹ as determined by        surface plasmon resonance.

Optionally, the variant has

-   -   I: a KD according to (a) and (d), a K_(d) according to (b) and        (e), and a K_(a) according to (c) and (f); or    -   II: a KD according to (a) and (g), a K_(d) according to (b) and        (h), and a K_(a) according to (c) and (i); or    -   III: a KD according to (a) and (j), a K_(d) according to (b) and        (k), and a K_(a) according to (c) and (l); or    -   IV: kinetics according to I and II; or    -   V: kinetics according to I and III; or    -   VI: kinetics according to I, II and III.

The invention also provides a ligand comprising a variant of anypreceding aspect or embodiment of the invention. For example, the ligandcan be a dual-specific ligand (see WO04003019 for examples ofdual-specific ligands). In one aspect, the invention provides amultispecific ligand comprising an anti-SA variant of any precedingaspect or embodiment of the invention and a binding moiety thatspecifically binds a target antigen other than SA. The binding moietycan be any binding moiety that specifically binds a target, eg, themoiety is an antibody, antibody fragment, scFv, Fab, dAb or a bindingmoiety comprising a non-immunoglobulin protein scaffold. Such moietiesare disclosed in detail in WO2008/096158 (see examples 17 to 25, whichdisclosure is incorporated herein by reference). Examples ofnon-immunoglobulin scaffolds are CTLA-4, lipocallin, staphylococcalprotein A (spA), Affibody™ Avimers™, adnectins, GroEL and fibronectin.

In one embodiment, a linker is provided between the anti-target bindingmoiety and the anti-SA single variant, the linker comprising the aminoacid sequence AST, optionally ASTSGPS. Alternative linkers are describedin WO2007085814 (incorporated herein by reference) and WO2008/096158(see the passage at page 135, line 12 to page 140, line 14, whichdisclosure and all sequences of linkers are expressly incorporatedherein by reference as though explicitly written herein and for use withthe present invention, and it is contemplated that any part of suchdisclosure can be incorporated into one or more claims herein).

In one embodiment of the multispecific ligand, the target antigen maybe, or be part of, polypeptides, proteins or nucleic acids, which may benaturally occurring or synthetic. In this respect, the ligand of theinvention may bind the target antigen and act as an antagonist oragonist (e.g., EPO receptor agonist). One skilled in the art willappreciate that the choice is large and varied. They may be forinstance, human or animal proteins, cytokines, cytokine receptors, wherecytokine receptors include receptors for cytokines, enzymes, co-factorsfor enzymes or DNA binding proteins. Suitable cytokines and growthfactors include, but are preferably not limited to: ApoE, Apo-SAA, BDNF,Cardiotrophin-1, EGF, EGF receptor, ENA-78, Eotaxin, Eotaxin-2,Exodus-2, EpoR, FGF-acidic, FGF-basic, fibroblast growth factor-10, FLT3ligand, Fractalkine (CX3C), GDNF, G-CSF, GM-CSF, GF-β1, insulin, IFN-γ,IGF-I, IGF-II, IL-1α, IL-1β, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8(72 a.a.), IL-8 (77 a.a.), IL-9, IL-10, IL-11, IL-12, IL-13, IL-15,IL-16, IL-17, IL-18 (IGIF), Inhibin α, Inhibin β, IP-10, keratinocytegrowth factor-2 (KGF-2), KGF, Leptin, LIF, Lymphotactin, Mullerianinhibitory substance, monocyte colony inhibitory factor, monocyteattractant protein, M-CSF, MDC (67 a.a.), MDC (69 a.a.), MCP-1 (MCAF),MCP-2, MCP-3, MCP-4, MDC (67 a.a.), MDC (69 a.a.), MIG, MIP-1α, MIP-1β,MIP-3α, MIP-3β, MIP-4, myeloid progenitor inhibitor factor-1 (MPIF-1),NAP-2, Neurturin, Nerve growth factor, β-NGF, NT-3, NT-4, Oncostatin M,PDGF-AA, PDGF-AB, PDGF-BB, PF-4, RANTES, SDF1α, SDF1β, SCF, SCGF, stemcell factor (SCF), TARC, TGF-α, TGF-β, TGF-β2, TGF-β3, tumour necrosisfactor (TNF), TNF-α, TNF-β, TNF receptor I, TNF receptor II, TNIL-1,TPO, VEGF, VEGF receptor 1, VEGF receptor 2, VEGF receptor 3, GCP-2,GRO/MGSA, GRO-β, GRO-γ, HCC1, 1-309, HER 1, HER 2, HER 3 and HER 4, CD4,human chemokine receptors CXCR4 or CCR5, non-structural protein type 3(NS3) from the hepatitis C virus, TNF-alpha, IgE, IFN-gamma, MMP-12,CEA, H. pylori, TB, influenza, Hepatitis E, MMP-12, internalizingreceptors that are over-expressed on certain cells, such as theepidermal growth factor receptor (EGFR), ErBb2 receptor on tumor cells,an internalising cellular receptor, LDL receptor, FGF2 receptor, ErbB2receptor, transferrin receptor, PDGF receptor, VEGF receptor, PsmAr, anextracellular matrix protein, elastin, fibronectin, laminin,α1-antitrypsin, tissue factor protease inhibitor, PDK1, GSK1, Bad,caspase-9, Forkhead, an antigen of Helicobacter pylori, an antigen ofMycobacterium tuberculosis, and an antigen of influenza virus. It willbe appreciated that this list is by no means exhaustive.

In one embodiment, the multispecific ligand comprises an anti-SA dAbvariant of the invention and an anti-TNFR1 binding moiety, eg, ananti-TNFR1 dAb. Optionally, the ligand has only one anti-TNFR1 bindingmoiety (eg, dAb) to reduce the chance of receptor cross-linking. In oneembodiment, the anti-SA dAb variant is DOM7h-11-3 or DOM7h-11-15 orDOM7h-11-15^(S12P).

In one embodiment, the anti-TNFR1 binding moiety is DOM1h-131-206disclosed in WO2008149148 (the amino acid sequence of which and thenucleotide sequence of which, as disclosed in that PCT application, areexpressly incorporated herein by reference as though explicitly writtenherein and for use with the present invention, and it is contemplatedthat any part of such disclosure can be incorporated into one or moreclaims herein). In one embodiment, the multispecific ligand comprises orconsists of the amino acid sequence of DOM1h-131-206 and the amino acidsequence of DOM7h-11-3 or DOM7h-11-15 or DOM7h-11-15^(S12P).

In one embodiment, the anti-TNFR1 binding moiety or dAb is any suchmoiety or dAb disclosed in co-pending application U.S. Ser. No.61/153,746, the disclosure of which is incorporated herein by reference.In one embodiment, the anti-TNFR1 binding moiety comprises an amino acidsequence that is at least 95% identical to the amino acid sequence ofDOM1h-574-156, DOM1h-574-72, DOM1h-574-109, DOM1h-574-138, DOM1h-574-162or DOM1h-574-180 or the amino acid sequence of any anti-TNFR1 dAbdisclosed in Table 3. In one embodiment, the multispecific ligandcomprises or consists of the amino acid sequence of DOM1h-574-156 andthe amino acid sequence of DOM7h-11-3 or DOM7h-11-15 orDOM7h-11-15^(S12P).

In one embodiment, the ligand of the invention is a fusion proteincomprising a variant of the invention fused directly or indirectly toone or more polypeptides. For example, the fusion protein can be a “drugfusion” as disclosed in WO2005/118642 (the disclosure of which isincorporated herein by reference), comprising a variant of the inventionand a polypeptide drug as defined in that PCT application.

As used herein, “drug” refers to any compound (e.g., small organicmolecule, nucleic acid, polypeptide) that can be administered to anindividual to produce a beneficial, therapeutic or diagnostic effectthrough binding to and/or altering the function of a biological targetmolecule in the individual. The target molecule can be an endogenoustarget molecule encoded by the individual's genome (e.g. an enzyme,receptor, growth factor, cytokine encoded by the individual's genome) oran exogenous target molecule encoded by the genome of a pathogen (e.g.an enzyme encoded by the genome of a virus, bacterium, fungus, nematodeor other pathogen). Suitable drugs for use in fusion proteins andconjugates comprising an anti-SA dAb variant of the invention aredisclosed in WO2005/118642 and WO2006/059106 (the entire disclosures ofwhich are incorporated herein by reference, and including the entirelist of specific drugs as though this list were expressly writtenherein, and it is contemplated that such incorporation providesdisclosure of specific drugs for inclusion in claims herein). Forexample, the drug can be glucagon-like peptide 1 (GLP-1) or a variant,interferon alpha 2b or a variant or exendin-4 or a variant.

In one embodiment, the invention provides a drug conjugate as definedand disclosed in WO2005/118642 and WO2006/059106, wherein the conjugatecomprises a variant of the invention. In one example, the drug iscovalently linked to the variant (eg, the variant and the drug areexpressed as part of a single polypeptide). Alternatively, in anexample, the drug is non-covalently bonded or associated with thevariant. The drug can be covalently or noncovalently bonded to thevariant directly or indirectly (e.g., through a suitable linker and/ornoncovalent binding of complementary binding partners (e.g., biotin andavidin)). When complementary binding partners are employed, one of thebinding partners can be covalently bonded to the drug directly orthrough a suitable linker moiety, and the complementary binding partnercan be covalently bonded to the variant directly or through a suitablelinker moiety. When the drug is a polypeptide or peptide, the drugcomposition can be a fusion protein, wherein the polypeptide or peptide,drug and the polypeptide binding moiety are discrete parts (moieties) ofa continuous polypeptide chain. As described herein, the polypeptidebinding moieties and polypeptide drug moieties can be directly bonded toeach other through a peptide bond, or linked through a suitable aminoacid, or peptide or polypeptide linker.

A ligand which contains one single variable domain (monomer) variant ofthe invention or more than one single variable domain (multimer, fusionprotein, conjugate, and dual specific ligand as defined herein) whichspecifically binds to serum albumin, can further comprise one or moreentities selected from, but preferably not limited to a label, a tag, anadditional single variable domain, a dAb, an antibody, an antibodyfragment, a marker and a drug. One or more of these entities can belocated at either the COOH terminus or at the N terminus or at both theN terminus and the COOH terminus of the ligand comprising the singlevariable domain, (either immunoglobulin or non-immunoglobulin singlevariable domain). One or more of these entities can be located at eitherthe COOH terminus, or the N terminus, or both the N terminus and theCOOH terminus of the single variable domain which specifically bindsserum albumin of the ligand which contains one single variable domain(monomer) or more than one single variable domains (multimer, fusionprotein, conjugate, and dual specific ligand as defined herein).Non-limiting examples of tags which can be positioned at one or both ofthese termini include a HA, his or a myc tag. The entities, includingone or more tags, labels and drugs, can be bound to the ligand whichcontains one single variable domain (monomer) or more than one singlevariable domain (multimer, fusion protein, conjugate, and dual specificligand as defined herein), which binds serum albumin, either directly orthrough linkers as described above.

An aspect of the invention provides a fusion product, eg, a fusionprotein or fusion with a peptide or conjugate with an NCE (new chemicalentity) drug, comprising a polypeptide drug fused or conjugated (for anNCE) to any variant as described above, optionally wherein the variantis DOM7h-11-15 or DOM7h-11-15^(S12P) (or a variant having an amino acidthat is at least 95, 96, 97, 98 or 99% identical to the amino acidsequence of DOM7h-11-15 or DOM7h-11-15^(S12P)) or DOM7h-11-12 (or avariant having an amino acid that is at least 95, 96, 97, 98 or 99%identical to the amino acid sequence of DOM7h-11-15 orDOM7h-11-15^(S12P)). DOM7h-11-15, DOM7h-11-15^(S12P) and DOM7h-11-12give only a modest drop in affinity when fused or conjugated to partner,making them useful in fusion products.

The invention provides a composition comprising a variant, fusionprotein, conjugate or ligand of any aspect of the invention and apharmaceutically acceptable diluent, carrier, exipient or vehicle.

Also encompassed herein is an isolated nucleic acid encoding any of thevariants, fusion proteins, conjugates or ligands described herein, e.g.,a ligand which contains one single variable domain (monomer) variant ofthe invention or more than one single variable domain (e.g., multimer,fusion protein, conjugate, and dual specific ligand as defined herein)variant which specifically binds to serum albumin, or which specificallybinds both human serum albumin and at least one non-human serum albumin,or functionally active fragments thereof. Also encompassed herein is avector and/or an expression vector, a host cell comprising the vector,e.g., a plant or animal cell and/or cell line transformed with a vector,a method of expressing and/or producing one or more variants, fusionproteins or ligands which contains one single variable domain (monomer)varuiant or more than one single variable domain variants (e.g.,multimer, fusion protein, conjugate, and dual specific ligand as definedherein) which specifically binds to serum albumin, or fragment(s)thereof encoded by said vectors, including in some instances culturingthe host cell so that the one or more variants, fusion proteins orligands or fragments thereof are expressed and optionally recovering theligand which contains one single variable domain (monomer) or more thanone single variable domain (e.g., multimer, fusion protein, conjugate,and dual specific ligand as defined herein) which specifically binds toserum albumin, from the host cell culture medium. Also encompassed aremethods of contacting a ligand described herein with serum albumin,including serum albumin and/or non-human serum albumin(s), and/or one ormore targets other than serum albumin, where the targets includebiologically active molecules, and include animal proteins, cytokines aslisted above, and include methods where the contacting is in vitro aswell as administering any of the variants, fusion proteins or ligandsdescribed herein to an individual host animal or cell in vivo and/or exvivo. Preferably, administering ligands described herein which comprisesa single variable domain (immunoglobulin or non-immunoglobulin) directedto serum albumin and/or non-human serum albumin(s), and one or moredomains directed to one or more targets other than serum albumin, willincrease the half life, including the T beta and/or terminal half life,of the anti-target ligand. Nucleic acid molecules encoding the variants,fusion proteins or single domain containing ligands or fragmentsthereof, including functional fragments thereof, are contemplatedherein. Vectors encoding the nucleic acid molecules, including butpreferably not limited to expression vectors, are contemplated herein,as are host cells from a cell line or organism containing one or more ofthese expression vectors. Also contemplated are methods of producing anyvariant, fusion protein or ligand, including, but preferably not limitedto any of the aforementioned nucleic acids, vectors and host cells.

An aspect of the invention provides a nucleic acid comprising anucleotide sequence encoding a variant according to the invention or amultispecific ligand of the invention or fusion protein of theinvention.

An aspect of the invention provides a nucleic acid comprising thenucleotide sequence of a DOM7h-11 variant selected from DOM7h-11-3,DOM7h-11-15, DOM7h-11-15^(S12P), DOM7h-11-12, DOM7h-11-18 andDOM7h-11-19 or a nucleotide sequence that is at least 70, 75, 80, 85,90, 95, 96, 97, 98 or 99% identical to said selected sequence.

An aspect of the invention provides a vector comprising the nucleic acidof the invention. An aspect of the invention provides an isolated hostcell comprising the vector.

Reference is made to WO2008/096158 for details of library vectorsystems, combining single variable domains, characterization of dualspecific ligands, structure of dual specific ligands, scaffolds for usein constructing dual specific ligands, uses of anti-serum albumin dAbsand multispecific ligands and half-life-enhanced ligands, andcompositions and formulations of comprising anti-serum albumin dAbs.These disclosures are incorporated herein by reference to provideguidance for use with the present invention, including for variants,ligands, fusion proteins, conjugates, nucleic acids, vectors, hosts andcompositions of the present invention.

DOM7h-14 variant sequences, which are not according to the invention,are disclosed in a co-pending US provisional patent application entitledIMPROVED ANTI-SERUM ALBUMIN BINDING VARIANTS, filed on the same day asthe present application. These sequences of DOM7h-14 variants (SEQ IDNO:s 1-10 in the co-pending application) are incorporated herein byreference as though explicitly written herein.

Sequences

TABLE 1 Amino Acid Sequences of DOM7h-11 Variant dAbs DOM7h-11-12 (SEQID NO: 1) DIQMTQSPSSLSASVGDRVTITCRASRPIGTMLSWYQQKPGKAPKLLILFGSRLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCAQAGTHPTTFGQ GTKVEIKR DOM7h-11-15(SEQ ID NO: 2) DIQMTQSPSSLSASVGDRVTITCRASRPIGTMLSWYQQKPGKAPKLLILAFSRLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCAQAGTHPTTFGQ GTKVEIKR DOM7h-11-18(SEQ ID NO: 3) DIQMTQSPSSLSASVGDRVTITCRASRPIGTMLSWYQQKPGKAPKLLIWFGSRLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYHCAQAGTHPTTFGQ GTKVEIKR DOM7h-11-19(SEQ ID NO: 4) DIQMTQSPSSLSASVGDRVTITCRASRPIGTMLSWYQQKPGKAPKLLILFGSRLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCAQTGTHPTTFGQ GTKVEIKR DOM7h-11-3(SEQ ID NO: 5) DIQMTQSPSSLSASVGDRVTITCRASRPIGTTLSWYQQKPGKAPKLLILWNSRLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCAQAGTHPTTFGQ GTKVEIKR

TABLE 2 Nucleotide Sequences of DOM7h-11 Variant dAbs DOM7h-11-12 (SEQID NO: 6) GACATCCAGA TGACCCAGTC TCCATCCTCC CTGTCTGCAT CTGTAGGAGA CCGTGTCACC ATCACTTGCC GGGCAAGTCG TCCGATTGGG ACGATGTTAA GTTGGTACCA GC AGAAACCAGGGAAAGCCC CTAAGCTCCT GATCTTGTTT GGTTCCCGGT TGCAAAGT GG GGTCCCATCACGTTTCAGTG GCAGTGGATC TGGGACAGAT TTCACTCTCA CCAT CAGCAG TCTGCAACCTGAAGATTTTG CTACGTACTA CTGTGCGCAG GCTGGGACGC ATCCTACGAC GTTCGGCCAAGGGACCAAGG TGGAAATCAA ACGG DOM7h-11-15 (SEQ ID NO: 7) GACATCCAGATGACCCAGTC TCCATCCTCC CTGTCTGCAT CTGTAGGAGA CCGTGT CACC ATCACTTGCCGGGCAAGTCG TCCGATTGGG ACGATGTTAA GTTGGTACCA GC AGAAACCA GGGAAAGCCCCTAAGCTCCT GATCCTTGCT TTTTCCCGTT TGCAAAGT GG GGTCCCATCA CGTTTCAGTGGCAGTGGATC TGGGACAGAT TTCACTCTCA CCAT CAGCAG TCTGCAACCT GAAGATTTTGCTACGTACTA CTGCGCGCAG GCTGGGACGC ATCCTACGAC GTTCGGCCAA GGGACCAAGGTGGAAATCAA ACGG DOM7h-11-18 (SEQ ID NO: 8) GACATCCAGA TGACCCAGTCTCCATCCTCC CTGTCTGCAT CTGTAGGAGA CCGTGT CACC ATCACTTGCC GGGCAAGTCGTCCGATTGGG ACGATGTTAA GTTGGTACCA GC AGAAACCA GGGAAAGCCC CAAAGCTCCTGATCTGGTTT GGTTCCCGGT TGCAAAGT GG GGTCCCATCA CGTTTCAGTG GCAGTGGATCTGGGACAGAT TTCACTCTCA CCAT CAGCAG TCTGCAACCT GAAGATTTTG CTACGTACCACTGTGCGCAG GCGGGGACGC ATCCTACGAC GTTCGGCCAA GGGACCAAGG TGGAAATCAA ACGGDOM7h-11-19 (SEQ ID NO: 9) GACATCCAGA TGACCCAGTC TCCATCCTCC CTGTCTGCATCTGTAGGAGA CCGTGT CACC ATCACTTGCC GGGCAAGTCG TCCGATTGGG ACGATGTTAAGTTGGTACCA GC AGAAACCA GGGAAAGCCC CTAAGCTCCT GATCTTGTTT GGTTCCCGGTTGCAAAGT GG GGTCCCATCA CGTTTCAGTG GCAGTGGATC TGGGACGGAT TTCACTCTCA CCATCAGCAG TCTGCAACCT GAAGATTTTG CTACGTACTA CTGTGCGCAG ACTGGGACGC ATCCCACGACGTTCGGCCAA GGGACCAAGG TGGAAATCAA ACGG DOM7h-11-3 (SEQ ID NO: 10)GACATCCAGA TGACCCAGTC TCCATCCTCC CTGTCTGCAT CTGTAGGAGA CCGTGT CACCATCACTTGCC GGGCAAGTCG TCCGATTGGG ACGACGTTAA GTTGGTACCA GC AGAAACCAGGGAAAGCCC CTAAGCTCCT GATCCTTTGG AATTCCCGTT TGCAAAGT GG GGTCCCATCACGTTTCAGTG GCAGTGGATC TGGGACAGAT TTCACTCTCA CCAT CAGCAG TCTGCAACCTGAAGATTTTG CTACGTACTA CTGTGCGCAG GCTGGGACGC ATCCTACGAC GTTCGGCCAAGGGACCAAGG TGGAAATCAA ACGG

TABLE 3 Amino Acid Sequences of anti-TNFR1 dAbs >DOM1h-509 (SEQ ID NO:11) EVQLLESGGGLVQPGGSLRLSCAASGFTFSQYRMHWVRQAPGKSLEWVSSIDTRGSSTYYADPVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKAVTMFSPFFDYWGQGTLVTVSS >DOM1h-510 (SEQ ID NO: 12)EVQLLESGGGLVQPGGSLRLSCAASGFTFADYGMRWVRQAPGKGLEWVSSITRTGRVTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKWRNRHGEYLADFDYWGQGTLVTVSS >DOM1h-543 (SEQ ID NO: 13)EVQLLESGGGLVQPGGSLRLSCAASGFTFMRYRMHWVRQAPGKGLEWVSSIDSNGSSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKDRTERSPVFDYWGQGTLVTVSS >DOM1h-549 (SEQ ID NO: 14)EVQLLESGGGLVQPGGSLRLSCAASGFTFVDYEMHWVRQAPGKGLEWVSSISESGTTTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKRRFSASTFDYWGQGTLVTVSS >DOM1h-574 (SEQ ID NO: 15)EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISNTGGHTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKYTGHWEPFDYWGQGTLVTVSS >DOM1h-574-1 (SEQ ID NO: 16)EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISNTGGHTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKYTGRWEPYDYWGQGTLVTVSS >DOM1h-574-2 (SEQ ID NO: 17)EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISNTGGHTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKYTGRWEPFDYWGQGTLVTVSS >DOM1h-574-7 (SEQ ID NO: 18)EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISNTGGHTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWEPFDYWGQGTLVTVSS >DOM1h-574-8 (SEQ ID NO: 19)EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGPEWVSQISNTGGHTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWEPFDYWGQGTLVTVSS >DOM1h-574-9 (SEQ ID NO: 20)EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISNTGGHTYYADSVKGRFTISRDNSKNTLYMQMNSLRAEDTAVYYCAIYTGRWEPFDYWGQGTLVTVSS >DOM1h-574-10 (SEQ ID NO: 21)EVQLLESGGGLVQPGGSLRLSCAASGFTFGKYSMGWVRQAPGKDLEWVSQISNTGGHTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWEPFDYWGQGTLVTVSS >DOM1h-574-11 (SEQ ID NO: 22)EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISNTGGHTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKYTGRWEPFDHWGQGTLVTVSS >DOM1h-574-12 (SEQ ID NO: 23)EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISNTGDHTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKYTGRWEPFDYWGQGTLVTVSS >DOM1h-574-13 (SEQ ID NO: 24)EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISNTGDRTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKYTGRWEPFDYWGQGTLVTVSS >DOM1h-574-14 (SEQ ID NO: 25)EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISNTGDRTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWEPFDYWGQGTLVTVSS >DOM1h-574-15 (SEQ ID NO: 26)EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISNTGDHTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWEPFDYWGQGTLVTVSS >DOM1h-574-16 (SEQ ID NO: 27)EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGPEWVSQISNTGDRTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWEPFDYWGQGTLVTVSS >DOM1h-574-17 (SEQ ID NO: 28)EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGPEWVSQISNTGDHTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWEPFDYWGQGTLVTVSS >DOM1h-574-18 (SEQ ID NO: 29)EVQLLESGGGLVQPGGSLRLSCAASGFTFGKYSMGWVRQAPGKDLEWVSQISNTGDRTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWEPFDYWGQGTLVTVSS >DOM1h-574-19 (SEQ ID NO: 30)EVQLLESGGGLVQPGGSLRLSCAASGFTFGKYSMGWVRQAPGKDLEWVSQISNTGDHTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWEPFDYWGQGTLVTVSS >DOM1h-574-25 (SEQ ID NO: 31)EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISNTGDRTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWEPFVYWGQGTLVTVSS >DOM1h-574-26 (SEQ ID NO: 32)EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISNTGDRTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWEPFEYWGQGTLVTVSS >DOM1h-574-27 (SEQ ID NO: 33)EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISNTGDRTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWKPFEYWGQGTLVTVSS >DOM1h-574-28 (SEQ ID NO: 34)EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISNTGDRTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWVPFEYWGQGTLVTVSS >DOM1h-574-29 (SEQ ID NO: 35)EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISNTGDRTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWRPFEYWGQGTLVTVSS >DOM1h-574-30 (SEQ ID NO: 36)EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQIANTGDRRYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAAYYCAIYTGRWEPFDYWGQGTLVTVSS >DOM1h-574-31 (SEQ ID NO: 37)EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISNTADRTYYAHSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWEPFNYWGQGTLVTVSS >DOM1h-574-32 (SEQ ID NO: 38)EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISNTGDRTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWAPFEYWGQGTLVTVSS >DOM1h-574-33 (SEQ ID NO: 39)EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISNTGDRTYYADSVKGRFTISRDNSKNSLYLQMNSLRAEDTAVYYCAIYTGRWVPFDNWGQGTLVTVSS >DOM1h-574-35 (SEQ ID NO: 40)EVQLLESGGGLVQPGGSLRLSCAASGFTFITYSMGWVRQAPGKGLEWVSQISNTGDRTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWEPFQYWGQGTLVTVSS >DOM1h-574-36 (SEQ ID NO: 41)EVQLLESGGGLVQPGGSLRLSCAASGFTFGKYSMGWVRQAPGKGLEWVSQISNTGDRTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWEPFDYWGQGTLVTVSS >DOM1h-574-37 (SEQ ID NO: 42)EVQLLESGGGLVQPGGSLRLSCAASGFTFFKYSMGWVRQAPGKGLEWVSQISNTGDRTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWEPFDYWGQGTLVTVSS >DOM1h-574-38 (SEQ ID NO: 43)EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISDTGDRRYYDDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWEPFDYWGQGTLVTVSS >DOM1h-574-39 (SEQ ID NO: 44)EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISNTGDRRYYADAVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWEPFDYWGQGTLVTVSS >DOM1h-574-40 (SEQ ID NO: 45)EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISNTGDRTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWEPFKYWGQGTLVTVSS >DOM1h-574-53 (SEQ ID NO: 46)EVQLLESGGGLVQPGGSLRLSCAASGFTFSKYSMGWVRQAPGKGLEWVSQISNTGERRYYADSVKGRFTISRDNPKNTLYLQMNSLRAEDTAVYYCAIYTGRWEPFEYWGQGTLVTVSS >DOM1h-574-54 (SEQ ID NO: 47)EVQLLESGGGLVQPGGSLRLSCAASGFTFVNYSMGWVRQAPGKGLEWVSQISNTGDRTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWEPYEYWGQGTLVTVTS >DOM1h-574-65 (SEQ ID NO: 48)EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQIANTGDRRYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWEPFVYWGQGTLVTVSS >DOM1h-574-66 (SEQ ID NO: 49)EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQIANTGDRRYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWKPFEYWGQGTLVTVSS >DOM1h-574-67 (SEQ ID NO: 50)EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQIANTGDRRYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWVPFEYWGQGTLVTVSS >DOM1h-574-68 (SEQ ID NO: 51)EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQIANTGDRRYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWRPFEYWGQGTLVTVSS >DOM1h-574-69 (SEQ ID NO: 52)EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQIANTGDRRYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWAPFEYWGQGTLVTVSS >DOM1h-574-70 (SEQ ID NO: 53)EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISNTADRTYYAHSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAVYTGRWEPFVYWGQGTLVTVSS >DOM1h-574-71 (SEQ ID NO: 54)EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISNTADRTYYAHSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWKPFEYWGQGTLVTVSS >DOM1h-574-72 (SEQ ID NO: 55)EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISNTADRTYYAHSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWVPFEYWGQGTLVTVSS >DOM1h-574-73 (SEQ ID NO: 56)EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISNTADRTYYAHSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWRPFEYWGQGTLVTVSS >DOM1h-574-74 (SEQ ID NO: 57)EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISNTADRTYYAHSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWAPFEYWGQGTLVTVSS >DOM1h-574-75 (SEQ ID NO: 58)EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISDTGDRRYYDDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWEPFVYWGQGTLVTVSS >DOM1h-574-76 (SEQ ID NO: 59)EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISDTGDRRYYDDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWKPFEYWGQGTLVTVSS >DOM1h-574-77 (SEQ ID NO: 60)EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISDTGDRRYYDDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWVPFEYWGQGTLVTVSS >DOM1h-574-78 (SEQ ID NO: 61)EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISDTGDRRYYDDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWRPFEYWGQGTLVTVSS >DOM1h-574-79 (SEQ ID NO: 62)EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISDTGDRRYYDDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWAPFEYWGQGTLVTVSS >DOM1h-574-84 (SEQ ID NO: 63)EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISNTGDRRYYADAVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWEPFVYWGQGTLVTVSS >DOM1h-574-85 (SEQ ID NO: 64)EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISNTGDRRYYADAVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWKPFEYWGQGTLVTVSS >DOM1h-574-86 (SEQ ID NO: 65)EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISNTGDRRYYADAVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWVPFEYWGQGTLVTVSS >DOM1h-574-87 (SEQ ID NO: 66)EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISNTGDRRYYADAVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWRPFEYWGQGTLVTVSS >DOM1h-574-88 (SEQ ID NO: 67)EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISNTGDRRYYADAVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWAPFEYWGQGTLVTVSS >DOM1h-574-90 (SEQ ID NO: 68)EVQLLESGGGLVQPGGSLRLSCAASGFTFLKFSMGWVRQAPGKGLEWVSQIANTGDRRYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWAPFEYWGQGTLVTVSS >DOM1h-574-91 (SEQ ID NO: 69)EVQLLESGGGLVQPGGSLRLSCAASGFTFLKYSMGWVRQAPGKGLEWVSQISNTADRTYYAHSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWAPFEYWGQGTLVTVSS >DOM1h-574-92 (SEQ ID NO: 70)EVQLLESGGGLVQPGGSLRLSCAASGFTFFKYSMGWVRQAPGKGLEWVSQISDTGDRRYYDDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWEPFVYWGQGTLVTVSS >DOM1h-574-93 (SEQ ID NO: 71)EVQLLESGGGLVQPGGSLRLSCAASGFTFLKYSMGWVRQAPGKGLEWVSQISDTGDRRYYDDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWEPFVYWGQGTLVTVSS >DOM1h-574-94 (SEQ ID NO: 72)EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQIANTGDRRYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAAYYCAIYTGRWPDFDYWGQGTLVTVSS >DOM1h-574-95 (SEQ ID NO: 73)EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQIANTGDRRYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAAYYCAIYTGRWPDFEYWGQGTLVTVSS >DOM1h-574-96 (SEQ ID NO: 74)EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISNTADRTYYAHSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWPDFDYWGQGTLVTVSS >DOM1h-574-97 (SEQ ID NO: 75)EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISNTADRTYYAHSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWPDFEYWGQGTLVTVSS >DOM1h-574-98 (SEQ ID NO: 76)EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISDTGDRRYYDDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWPDFDYWGQGTLVTVSS >DOM1h-574-99 (SEQ ID NO: 77)EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISDTGDRRYYDDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWPDFEYWGQGTLVTVSS >DOM1h-574-100 (SEQ ID NO: 78)EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGPEWVSQISAWGDRTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWEPFDYWGQGTLVTVSS >DOM1h-574-101 (SEQ ID NO: 79)EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGPEWVSQISDGGQRTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWEPFDYWGQGTLVTVSS >DOM1h-574-102 (SEQ ID NO: 80)EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGPEWVSQISDSGYRTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWEPFDYWGQGTLVTVSS >DOM1h-574-103 (SEQ ID NO: 81)EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGPEWVSQISDGGTRTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWEPFDYWGQGTLVTVSS >DOM1h-574-104 (SEQ ID NO: 82)EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGPEWVSQISDKGTRTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWEPFDYWGQGTLVTVSS >DOM1h-574-105 (SEQ ID NO: 83)EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGPEWVSQISETGRRTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWEPFDYWGQGTLVTVSS >DOM1h-574-106 (SEQ ID NO: 84)EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQINNTGSTTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWEPFDYWGQGTLVTVSS >DOM1h-574-107 (SEQ ID NO: 85)EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGPEWVSQISNTADRTYYAHSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWVPFEYWGQGTLVTVSS >DOM1h-574-108 (SEQ ID NO: 86)EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGPEWVSQISNTADRTYYAHSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWAPFEYWGQGTLVTVSS >DOM1h-574-109 (SEQ ID NO: 87)EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISDTADRTYYAHSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWVPFEYWGQGTLVTVSS >DOM1h-574-110 (SEQ ID NO: 88)EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISDTADRTYYAHSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWAPFEYWGQGTLVTVSS >DOM1h-574-111 (SEQ ID NO: 89)EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISDTADRTYYDDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWRPFEYWGQGTLVTVSS >DOM1h-574-112 (SEQ ID NO: 90)EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISDTADRTYYTHSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWAPFEYWGQGTLVTVSS >DOM1h-574-113 (SEQ ID NO: 91)EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISNTADRRYYAHSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWAPFEYWGQGTLVTVSS >DOM1h-574-114 (SEQ ID NO: 92)EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQILNTADRTYYDHSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWAPFEYWGQGTLVTVSS >DOM1h-574-115 (SEQ ID NO: 93)EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISNTADRTYYDHSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWAPFEYWGQGTLVTVSS >DOM1h-574-116 (SEQ ID NO: 94)EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISDTADRRYYAHSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWAPFEYWGQGTLVTVSS >DOM1h-574-117 (SEQ ID NO: 95)EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISDTADRRYYDHSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWAPFEYWGQGTLVTVSS >DOM1h-574-118 (SEQ ID NO: 96)EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISNTADRTYYAHSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAVYTGRWVSFEYWGQGTLVTVSS >DOM1h-574-119 (SEQ ID NO: 97)EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISNTADRTYYAHSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCALYTGRWVSFEYWGQGTLVTVSS >DOM1h-574-120 (SEQ ID NO: 98)EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISNTADRTYYAHSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAVYTGRWVPFEYWGQGTLVTVSS >DOM1h-574-121 (SEQ ID NO: 99)EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISNTADRTYYAHSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCALYTGRWVPFEYWGQGTLVTVSS >DOM1h-574-122 (SEQ ID NO: 100)EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQIANTADRRYYAHSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWAPFEYWGQGTLVTVSS >DOM1h-574-123 (SEQ ID NO: 101)EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISNTADRRYYADAVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWEPFVYWGQGTLVTVSS >DOM1h-574-124 (SEQ ID NO: 102)EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISNTGDRRYYAHAVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWEPFVYWGQGTLVTVSS >DOM1h-574-125 (SEQ ID NO: 103)EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQIANTADRRYYADAVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWEPFVYWGQGTLVTVSS >DOM1h-574-126 (SEQ ID NO: 104)EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQIANTGDRRYYAHAVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWEPFVYWGQGTLVTVSS >DOM1h-574-127 (SEQ ID NO: 105)EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISNTADRRYYAHAVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWEPFVYWGQGTLVTVSS >DOM1h-574-128 (SEQ ID NO: 106)EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQIANTADRRYYAHAVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWEPFVYWGQGTLVTVSS >DOM1h-574-129 (SEQ ID NO: 107)EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQIVNTGDRRYYADAVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWEPFVYWGQGTLVTVSS >DOM1h-574-130 (SEQ ID NO: 108)EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQIANTGDRRYYADAVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWEPFVYWGQGTLVTVSS >DOM1h-574-131 (SEQ ID NO: 109)EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISDTADRTYYDHSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWAPFEYWGQGTLVTVSS >DOM1h-574-132 (SEQ ID NO: 110)EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISDTADRTYYDHSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWRPFEYWGQGTLVTVSS >DOM1h-574-133 (SEQ ID NO: 111)EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISDTADRTYYDHSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWEPFVYWGQGTLVTVSS >DOM1h-574-134 (SEQ ID NO: 112)EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISDTADRTYYSHSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWVPFEYWGQGTLVTVSS >DOM1h-574-135 (SEQ ID NO: 113)EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISDTADRTYYTHSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWVPFEYWGQGTLVTVSS >DOM1h-574-137 (SEQ ID NO: 114)EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISDTADRTYYTDAVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWEPFVYWGQGTLVTVSS >DOM1h-574-138 (SEQ ID NO: 115)EVQLLESGGGLVQPGGSLRLSCAASGFTFFKYSMGWVRQAPGKGLEWVSQISDTADRTYYAHSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWAPFEYWGQGTLVTVSS >DOM1h-574-139 (SEQ ID NO: 116)EVQLLESGGGLVQPGGSLRLSCAASGFTFLKYSMGWVRQAPGKGLEWVSQISDTADRTYYAHSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWAPFEYWGQGTLVTVSS >DOM1h-574-140 (SEQ ID NO: 117)EVQLLESGGGLVQPGGSLRLSCAASGFTFFKYSMGWVRQAPGKGLEWVSQIADTGDRRYYDDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWEPFVYWGQGTLVTVSS >DOM1h-574-141 (SEQ ID NO: 118)EVQLLESGGGLVQPGGSLRLSCAASGFTFFKYSMGWVRQAPGKGLEWVSQISDTADRRYYDDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWEPFVYWGQGTLVTVSS >DOM1h-574-142 (SEQ ID NO: 119)EVQLLESGGGLVQPGGSLRLSCAASGFTFFKYSMGWVRQAPGKGLEWVSQISDTGDRRYYDHSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWEPFVYWGQGTLVTVSS >DOM1h-574-143 (SEQ ID NO: 120)EVQLLESGGGLVQPGGSLRLSCAASGFTFFKYSMGWVRQAPGKGLEWVSQISDTGDRRYYDDAVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWEPFVYWGQGTLVTVSS >DOM1h-574-144 (SEQ ID NO: 121)EVQLLESGGGLVQPGGSLRLSCAASGFTFFKYSMGWVRQAPGKGLEWVSQIADTADRRYYDDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWEPFVYWGQGTLVTVSS >DOM1h-574-145 (SEQ ID NO: 122)EVQLLESGGGLVQPGGSLRLSCAASGFTFFKYSMGWVRQAPGKGLEWVSQIADTGDRRYYDHSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWEPFVYWGQGTLVTVSS >DOM1h-574-146 (SEQ ID NO: 123)EVQLLESGGGLVQPGGSLRLSCAASGFTFFKYSMGWVRQAPGKGLEWVSQIADTGDRRYYDDAVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWEPFVYWGQGTLVTVSS >DOM1h-574-147 (SEQ ID NO: 124)EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISDTADRTYYAHSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWGPFVYWGQGTLVTVSS >DOM1h-574-148 (SEQ ID NO: 125)EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISDTADRTYYAHSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWVPFAYWGQGTLVTVSS >DOM1h-574-149 (SEQ ID NO: 126)EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISDTADRTYYAHSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWGPFQYWGQGTLVTVSS >DOM1h-574-150 (SEQ ID NO: 127)EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISDTADRTYYAHSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWEPFQYWGQGTLVTVSS >DOM1h-574-151 (SEQ ID NO: 128)EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISDTADRTYYAHSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWAPFEYWGQGTLVTVSS >DOM1h-574-152 (SEQ ID NO: 129)EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISDTADRTYYAHSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWAPFQYWGQGTLVTVSS >DOM1h-574-153 (SEQ ID NO: 130)EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISDTADRTYYAHSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWVPFQYWGQGTLVTVSS >DOM1h-574-154 (SEQ ID NO: 131)EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISDTGDRRYYDHSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWAPFEYWGQGTLVTVSS >DOM1h-574-155 (SEQ ID NO: 132)EVQLLESGGGLVQPGGSLRLSCAASGFTFLKYSMGWVRQAPGKGLEWVSQISDTADRTYYAHSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWVPFEYWGQGTLVTVSS >DOM1h-574-156 (SEQ ID NO: 133)EVQLLESGGGLVQPGGSLRLSCAASGFTFFKYSMGWVRQAPGKGLEWVSQISDTADRTYYAHSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWVPFEYWGQGTLVTVSS >DOM1h-574-157 (SEQ ID NO: 134)EVQLLESGGGLVQPGGSLRLSCAASGFTFLKYSMGWVRQAPGKGLEWVSQISDTADRTYYDHSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWRPFEYWGQGTLVTVSS >DOM1h-574-158 (SEQ ID NO: 135)EVQLLESGGGLVQPGGSLRLSCAASGFTFFKYSMGWVRQAPGKGLEWVSQISDTADRTYYDHSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWRPFEYWGQGTLVTVSS >DOM1h-574-159 (SEQ ID NO: 136)EVQLLESGGGLVQPGGSLRLSCAASGFTFFKYSMGWVRQAPGKGLEWVSQISDTADRTYYDHSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWEPFVYWGQGTLVTVSS >DOM1h-574-160 (SEQ ID NO: 137)EVQLLESGGGLVQPGGSLRLSCAASGFTFLKYSMGWVRQAPGKGLEWVSQISDTADRTYYDHSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWEPFVYWGQGTLVTVSS >DOM1h-574-161 (SEQ ID NO: 138)EVQLLESGGGLVQPGGSLRLSCAASGFTFLKYSMGWVRQAPGKGLEWVSQISDTADRTYYSHSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWVPFEYWGQGTLVTVSS >DOM1h-574-162 (SEQ ID NO: 139)EVQLLESGGGLVQPGGSLRLSCAASGFTFFKYSMGWVRQAPGKGLEWVSQISDTADRTYYSHSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWVPFEYWGQGTLVTVSS >DOM1h-574-163 (SEQ ID NO: 140)EVQLLESGGGLVQPGGSLRLSCAASGFTFFKYSMGWVRQAPGKGLEWVSQISDTADRTYYTHSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWVPFEYWGQGTLVTVSS >DOM1h-574-164 (SEQ ID NO: 141)EVQLLESGGGLVQPGGSLRLSCAASGFTFLKYSMGWVRQAPGKGLEWVSQISDTADRTYYTHSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWVPFEYWGQGTLVTVSS >DOM1h-574-165 (SEQ ID NO: 142)EVQLLESGGGLVQPGGSLRLSCAASGFTFFKYSMGWVRQAPGKGLEWVSQISDTADRTYYAHSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWAPFEYWGQGTLVTVSS >DOM1h-574-166 (SEQ ID NO: 143)EVQLLESGGGLVQPGGSLRLSCAASGFTFLKYSMGWVRQAPGKGLEWVSQISDTADRTYYAHSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWAPFEYWGQGTLVTVSS >DOM1h-574-167 (SEQ ID NO: 144)EVQLLESGGGLVQPGGSLRLSCAASGFTFLKYSMGWVRQAPGKGLEWVSQISDTGDRRYYDHSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWAPFEYWGQGTLVTVSS >DOM1h-574-169 (SEQ ID NO: 145)EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQIADTADRTYYAHSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWVPFEYWGQGTLVTVSS >DOM1h-574-170 (SEQ ID NO: 146)EVQLLESGGGLVQPGGSLRLSCAASGFTFFKYSMGWVRQAPGKGLEWVSQISDTADRTYYAHAVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWVPFEYWGQGTLVTVSS >DOM1h-574-171 (SEQ ID NO: 147)EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQIADTADRTYYDHSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWVPFEYWGQGTLVTVSS >DOM1h-574-172 (SEQ ID NO: 148)EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQIADTADRTYYDHAVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWVPFEYWGQGTLVTVSS >DOM1h-574-173 (SEQ ID NO: 149)EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQIADTADRRYYAHSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWAPFEYWGQGTLVTVSS >DOM1h-574-174 (SEQ ID NO: 150)EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISDTADRRYYAHAVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWAPFEYWGQGTLVTVSS >DOM1h-574-175 (SEQ ID NO: 151)EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQIADTADRRYYAHAVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWAPFEYWGQGTLVTVSS >DOM1h-574-176 (SEQ ID NO: 152)EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISDTADRRYYDHAVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWAPFEYWGQGTLVTVSS >DOM1h-574-177 (SEQ ID NO: 153)EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQIADTADRRYYDHAVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWAPFEYWGQGTLVTVSS >DOM1h-574-178 (SEQ ID NO: 154)EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQIADTADRRYYDHSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWAPFEYWGQGTLVTVSS >DOM1h-574-179 (SEQ ID NO: 155)EVQLLESGGGLVQPGGSLRLSCAASGFTFFKYSMGWVRQAPGKGLEWVSQISDTADRRYYDDAVKGRFTITRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWEPFVYWGQGTLVTVSS >DOM1h-574-180 (SEQ ID NO: 156)EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISDTADRTYYAHAVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWVPFEYWGQGTLVTVSS >DOM1h-574-4 (SEQ ID NO: 157)EVQLLESGGGLVQPGGSLRLSCAASGFTFVKYSMGWVRQAPGKGLEWVSQISNTGGHTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKYTGRWEPFEYWGQGTLVTVSS >DOM1h-574-168 (SEQ ID NO: 158)EVQLLESGGGLVQPGGSLRLSCAASGFTFFKYSMGWVRQAPGKGLEWVSQISDTGDRRYYDHSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIYTGRWAPFEYWGQGTLVT VSS

TABLE 4 Nucleotide sequences of anti-TNFR1 dAbs >DOM1h-509 (SEQ ID NO:157) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTAGTCAGTATAGGATGCATTGGGTCCGCCAGGCTCCAGGGAAGAGTCTAGAGTGGGTCTCAAGTATTGATACTAGGGGTTCGTCTACATACTACGCAGACCCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGAAAGCTGTGACGATGTTTTCTCCTTTTTTTGACTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-510 (SEQ ID NO: 158)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTGCTGATTATGGGATGCGTTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCATCTATTACGCGGACTGGTCGTGTTACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGAAATGGCGGAATCGGCATGGTGAGTATCTTGCTGATTTTGACTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-543 (SEQ ID NO: 159)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTATGAGGTATAGGATGCATTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCATCGATTGATTCTAATGGTTCTAGTACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGAAAGATCGTACGGAGCGTTCGCCGGTTTTTGACTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-549 (SEQ ID NO: 160)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTGCAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTGTTGATTATGAGATGCATTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCATCTATTAGTGAGAGTGGTACGACGACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGAAACGTCGTTTTTCTGCTTCTACGTTTGACTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574 (SEQ ID NO: 161)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGAATACGGGTGGTCATACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGAAATATACGGGTCATTGGGAGCCTTTTGACTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-1 (SEQ ID NO: 162)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGAATACGGGTGGTCATACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGAAATATACGGGTCGTTGGGAGCCTTATGACTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-2 (SEQ ID NO: 163)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGAATACGGGTGGTCATACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGAAATATACGGGTCGTTGGGAGCCTTTTGACTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-4 (SEQ ID NO: 164)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGAATACGGGTGGTCATACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGAAATATACGGGTCGTTGGGAGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-180 (SEQ ID NO: 165)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGGATACTGCTGATCGTACATACTACGCACACGCGGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCTGAGGACACCGCGGTATATTACTGTGCGATATATACTGGGCGTTGGGTGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-7 (SEQ ID NO: 166)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGAATACGGGTGGTCATACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGATATATACGGGTCGTTGGGAGCCTTTTGACTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-8 (SEQ ID NO: 167)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGATGGGTCCGCCAGGCTCCAGGGAAAGGTCCAGAGTGGGTCTCACAGATTTCGAATACGGGTGGTCATACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGATATATACGGGTCGTTGGGAGCCTTTTGACTACTGGGGTCAGGGAACCCTGGTCACAGTCTCGAGC >DOM1h-574-9 (SEQ ID NO: 168)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGAATACGGGTGGTCATACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATATCCCGCGACAATTCCAAGAACACGCTGTATATGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGATATATACGGGTCGTTGGGAGCCTTTTGACTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-10 (SEQ ID NO: 169)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTGGTAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGATCTAGAGTGGGTCTCACAGATTTCGAATACGGGTGGTCATACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGATATATACGGGTCGTTGGGAGCCTTTTGACTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-11 (SEQ ID NO: 170)GAGGTGCAGCTGTTGGAGTCAGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGAATACGGGTGGTCATACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGAAATATACGGGTCGTTGGGAGCCTTTTGACCACTGGGGTCAGGGGACCCTGGTCACCGTCTCGAGC >DOM1h-574-12 (SEQ ID NO: 171)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGAATACGGGTGATCATACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGAAATATACGGGTCGTTGGGAGCCTTTTGACTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-13 (SEQ ID NO: 172)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGAATACGGGTGATCGTACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGAAATATACGGGTCGTTGGGAGCCTTTTGACTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-14 (SEQ ID NO: 173)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGAATACGGGTGATCGTACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGATATATACGGGTCGTTGGGAGCCTTTTGACTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-15 (SEQ ID NO: 174)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGAATACGGGTGATCATACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGATATATACGGGTCGTTGGGAGCCTTTTGACTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-16 (SEQ ID NO: 175)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGATGGGTCCGCCAGGCTCCAGGGAAAGGTCCAGAGTGGGTCTCACAGATTTCGAATACGGGTGATCGTACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGATATATACGGGTCGTTGGGAGCCTTTTGACTACTGGGGTCAGGGAACCCTGGTCACAGTCTCGAGC >DOM1h-574-17 (SEQ ID NO: 176)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGATGGGTCCGCCAGGCTCCAGGGAAAGGTCCAGAGTGGGTCTCACAGATTTCGAATACGGGTGATCATACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGATATATACGGGTCGTTGGGAGCCTTTTGACTACTGGGGTCAGGGAACCCTGGTCACAGTCTCGAGC >DOM1h-574-18 (SEQ ID NO: 177)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTGGTAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGATCTAGAGTGGGTCTCACAGATTTCGAATACGGGTGATCGTACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGATATATACGGGTCGTTGGGAGCCTTTTGACTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-19 (SEQ ID NO: 178)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTGGTAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGATCTAGAGTGGGTCTCACAGATTTCGAATACGGGTGATCATACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGATATATACGGGTCGTTGGGAGCCTTTTGACTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-25 (SEQ ID NO: 179)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGAATACGGGTGATCGTACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGATATATACGGGTCGTTGGGAGCCTTTTGTCTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-26 (SEQ ID NO: 180)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGAATACGGGTGATCGTACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCTGAGGACACCGCGGTATATTACTGTGCGATATATACGGGTCGTTGGGAGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-27 (SEQ ID NO: 181)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGAATACGGGTGATCGTACATACTACGCGGACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCTGAGGACACCGCGGTATATTACTGTGCGATATATACGGGTCGTTGGAAGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-28 (SEQ ID NO: 182)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGAATACGGGTGATCGTACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCTGAGGACACCGCGGTATATTACTGTGCGATATATACTGGGCGTTGGGTGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-29 (SEQ ID NO: 183)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGAATACGGGTGATCGTACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGATATATACGGGTCGTTGGAGGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-30 (SEQ ID NO: 184)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTGCGAATACGGGTGATCGTAGATACTACGCAGACTCTGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGCATATTACTGTGCGATATATACGGGTCGTTGGGAGCCTTTTGACTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-31 (SEQ ID NO: 185)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGAATACTGCTGATCGTACATACTACGCACACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGATATATACGGGTCGTTGGGAGCCTTTTAACTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-32 (SEQ ID NO: 186)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGAATACGGGTGATCGTACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGATATATACGGGTCGGTGGGCGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-33 (SEQ ID NO: 187)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGAATACGGGTGATCGTACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACTCGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGATATATACGGGTCGTTGGGTGCCTTTTGACAACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-35 (SEQ ID NO: 188)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTATTACGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGAATACGGGTGATCGTACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGATATATACGGGTCGTTGGGAGCCTTTTCAGTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-36 (SEQ ID NO: 189)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTGGTAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGAATACGGGTGATCGTACATACTACGCGGACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGATATATACGGGTCGTTGGGAGCCTTTTGACTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-37 (SEQ ID NO: 190)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTTTTAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGAATACGGGTGATCGTACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAAGACACCGCGGTATATTACTGTGCGATATATACGGGTCGTTGGGAGCCTTTTGACTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-38 (SEQ ID NO: 191)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGGATACGGGTGATCGTAGATACTACGATGACTCTGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGATATATACGGGTCGTTGGGAGCCTTTTGACTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-39 (SEQ ID NO: 192)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGAATACGGGTGATCGTAGATACTACGCAGACGCGGTGAAGGGGCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGATATATACGGGTCGTTGGGAGCCTTTTGACTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-40 (SEQ ID NO: 193)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGAATACGGGTGATCGTACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCTGAGGACACCGCGGTATATTACTGTGCGATATATACGGGTCGTTGGGAGCCTTTTAAGTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-53 (SEQ ID NO: 194)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTAGTAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGAATACGGGTGAGCGTAGATACTACGCAGACTCAGTGAAGGGCCGGTTCACCATCTCCCGCGACAATCCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGATATATACGGGTCGGTGGGAGCCTTTTGAATACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-54 (SEQ ID NO: 195)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAACTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGAATACGGGTGATCGTACATACTACGCGGACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGATATATACGGGTCGTTGGGAGCCTTATGAGTACTGGGGTCAGGGAACCCTGGTCACCGTCACGAGC >DOM1h-574-65 (SEQ ID NO: 196)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTGCGAATACGGGTGATCGTAGATACTACGCAGACTCTGTGAAGGGCCGGTTCACCATCTCCCGCGATAATTCCAAGAACACACTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGATATATACGGGTCGTTGGGAGCCTTTTGTCTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-66 (SEQ ID NO: 197)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTGCGAATACGGGTGATCGTAGATACTACGCAGACTCTGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGATATATACGGGTCGTTGGAAGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-67 (SEQ ID NO: 198)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTGCGAATACGGGTGATCGTAGATACTACGCAGACTCTGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCTGAGGACACCGCGGTATATTACTGTGCGATATATACTGGGCGTTGGGTGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-68 (SEQ ID NO: 199)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTGCGAATACGGGTGATCGTAGATACTACGCAGACTCTGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGATATATACGGGTCGTTGGAGGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-69 (SEQ ID NO: 200)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTGCGAATACGGGTGATCGTAGATACTACGCAGACTCTGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGATATATACGGGTCGGTGGGCGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-70 (SEQ ID NO: 201)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGAATACTGCTGATCGTACATACTACGCACACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGGTATATACGGGTCGTTGGGAGCCTTTTGTCTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-71 (SEQ ID NO: 202)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGAATACTGCTGATCGTACATACTACGCACACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCTGAGGACACCGCGGTATATTACTGTGCGATATATACGGGTCGTTGGAAGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-72 (SEQ ID NO: 203)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGAATACTGCTGATCGTACATACTACGCACACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCTGAGGACACCGCGGTATATTACTGTGCGATATATACTGGGCGTTGGGTGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-73 (SEQ ID NO: 204)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGAATACTGCTGATCGTACATACTACGCACACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGATATATACGGGTCGTTGGAGGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-74 (SEQ ID NO: 205)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGAATACTGCTGATCGTACATACTACGCACACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGATATATACGGGTCGGTGGGCGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-75 (SEQ ID NO: 206)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGGATACGGGTGATCGTAGATACTACGATGACTCTGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGATATATACGGGTCGTTGGGAGCCTTTTGTCTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-76 (SEQ ID NO: 207)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCAGGCCCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGGATACGGGTGATCGTAGATACTACGATGACTCTGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCTGAGGACACCGCGGTATATTACTGTGCGATATATACGGGTCGTTGGAAGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-77 (SEQ ID NO: 208)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGGATACGGGTGATCGTAGATACTACGATGACTCTGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGATATATACTGGGCGTTGGGTGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-78 (SEQ ID NO: 209)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGGATACGGGTGATCGTAGATACTACGATGACTCTGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGATATATACGGGTCGTTGGAGGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-79 (SEQ ID NO: 210)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGGATACGGGTGATCGTAGATACTACGATGACTCTGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGATATATACGGGTCGGTGGGCGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-84 (SEQ ID NO: 211)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGAATACGGGTGATCGTAGATACTACGCAGACGCGGTGAAGGGGCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGATATATACGGGTCGTTGGGAGCCTTTTGTCTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-85 (SEQ ID NO: 212)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGAATACGGGTGATCGTAGATACTACGCAGACGCGGTGAAGGGGCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCTGAGGACACCGCGGTATATTACTGTGCGATATATACGGGTCGTTGGAAGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-86 (SEQ ID NO: 213)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCAGGCCCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGAATACGGGTGATCGTAGATACTACGCAGACGCGGTGAAGGGGCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAAGACACCGCGGTATATTACTGTGCGATATATACTGGGCGTTGGGTGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-87 (SEQ ID NO: 214)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGAATACGGGTGATCGTAGATACTACGCAGACGCGGTGAAGGGGCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGATATATACGGGTCGTTGGAGGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-88 (SEQ ID NO: 215)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGAATACGGGTGATCGTAGATACTACGCAGACGCGGTGAAGGGGCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGATATATACGGGTCGGTGGGCGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-90 (SEQ ID NO: 216)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTTTGAAGTTTTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTGCGAATACGGGTGATCGTAGATACTACGCAGACTCTGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGATATATACGGGTCGGTGGGCGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-91 (SEQ ID NO: 217)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTTTGAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGAATACTGCTGATCGTACATACTACGCACACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGATATATACGGGTCGGTGGGCGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-92 (SEQ ID NO: 218)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTTTCAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGGATACGGGTGATCGTAGATACTACGATGACTCTGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGATATATACGGGTCGTTGGGAGCCTTTTGTCTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-93 (SEQ ID NO: 219)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTTTGAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGGATACGGGTGATCGTAGATACTACGATGACTCTGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGATATATACGGGTCGTTGGGAGCCTTTTGTCTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-94 (SEQ ID NO: 220)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTGCGAATACGGGTGATCGTAGATACTACGCAGACTCTGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGCATATTACTGTGCGATATATACGGGTCGGTGGCCCGACTTTGACTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-95 (SEQ ID NO: 221)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTGCGAATACGGGTGATCGTAGATACTACGCAGACTCTGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGCATATTACTGTGCGATATATACGGGTCGGTGGCCCGACTTTGAGTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-96 (SEQ ID NO: 222)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGAATACTGCTGATCGTACATACTACGCACACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGATATATACGGGTCGGTGGCCCGACTTTGACTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-97 (SEQ ID NO: 223)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGAATACTGCTGATCGTACATACTACGCACACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGATATATACGGGTCGGTGGCCCGACTTTGAGTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-98 (SEQ ID NO: 224)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGGATACGGGTGATCGTAGATACTACGATGACTCTGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGATATATACGGGTCGGTGGCCCGACTTTGACTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-99 (SEQ ID NO: 225)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGGATACGGGTGATCGTAGATACTACGATGACTCTGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGATATATACGGGTCGGTGGCCCGACTTTGAGTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-100 (SEQ ID NO: 226)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGATGGGTCCGCCAGGCTCCAGGGAAAGGTCCAGAGTGGGTCTCACAGATTTCGGCCTGGGGTGACAGGACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGATATATACGGGTCGTTGGGAGCCTTTTGACTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-101 (SEQ ID NO: 227)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAAGGTCCAGAGTGGGTCTCACAGATTTCGGACGGCGGTCAGAGGACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGATATATACGGGTCGTTGGGAGCCTTTTGACTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-102 (SEQ ID NO: 228)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGATGGGTCCGCCAGGCTCCAGGGAAAGGTCCAGAGTGGGTCTCACAGATTTCGGACTCCGGTTACCGCACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGATATATACGGGTCGTTGGGAGCCTTTTGACTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-103 (SEQ ID NO: 229)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCCAGAGTGGGTCTCACAGATTTCGGACGGGGGTACGCGGACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGATATATACGGGTCGTTGGGAGCCTTTTGACTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-104 (SEQ ID NO: 230)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGATGGGTCCGCCAGGCTCCAGGGAAAGGTCCAGAGTGGGTCTCACAGATTTCGGACAAGGGTACGCGCACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGATATATACGGGTCGTTGGGAGCCTTTTGACTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-105 (SEQ ID NO: 231)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGATGGGTCCGCCAGGCTCCAGGGAAAGGTCCAGAGTGGGTCTCACAGATTTCGGAGACCGGTCGCAGGACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGATATATACGGGTCGTTGGGAGCCTTTTGACTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-106 (SEQ ID NO: 232)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTAACAATACGGGTTCGACCACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGATATATACGGGTCGTTGGGAGCCTTTTGACTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-107 (SEQ ID NO: 233)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCCAGAGTGGGTCTCACAGATTTCGAATACTGCTGATCGTACATACTACGCACACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCTGAGGACACCGCGGTATATTACTGTGCGATATATACTGGGCGTTGGGTGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-108 (SEQ ID NO: 234)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCCAGAGTGGGTCTCACAGATTTCGAATACTGCTGATCGTACATACTACGCACACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGATATATACGGGTCGGTGGGCGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-109 (SEQ ID NO: 235)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGGATACTGCTGATCGTACATACTACGCACACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCTGAGGACACCGCGGTATATTACTGTGCGATATATACTGGGCGTTGGGTGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-110 (SEQ ID NO: 236)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGGATACTGCTGATCGTACATACTACGCACACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGATATATACGGGTCGGTGGGCGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-111 (SEQ ID NO: 237)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGGATACTGCTGATCGTACATACTACGATGACTCTGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGATATATACGGGTCGTTGGAGGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-112 (SEQ ID NO: 238)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGGATACTGCTGATCGTACATACTACACACACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGATATATACGGGTCGGTGGGCGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-113 (SEQ ID NO: 239)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGAATACTGCTGATCGCAGATACTACGCACACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGATATATACGGGTCGGTGGGCGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-114 (SEQ ID NO: 240)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTTGAATACTGCTGATCGTACATACTACGATCACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGATATATACGGGTCGGTGGGCGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-115 (SEQ ID NO: 241)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGAATACTGCTGATCGTACATACTACGATCACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGATATATACGGGTCGGTGGGCGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-116 (SEQ ID NO: 242)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGGATACTGCTGATCGTAGATACTACGCACACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGATATATACGGGTCGGTGGGCGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-117 (SEQ ID NO: 243)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGGATACTGCTGATCGTAGATACTACGATCACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGATATATACGGGTCGGTGGGCGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-118 (SEQ ID NO: 244)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGAATACTGCTGATCGTACATACTACGCACACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGGTATATACTGGGCGTTGGGTGTCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-119 (SEQ ID NO: 245)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGAATACTGCTGATCGTACATACTACGCACACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGCTATATACTGGGCGTTGGGTGTCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-120 (SEQ ID NO: 246)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGAATACTGCTGATCGTACATACTACGCACACTCCGTGAAGGGCCGGTTTACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGGTATATACTGGGCGTTGGGTGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-121 (SEQ ID NO: 247)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGAATACTGCTGATCGTACATACTACGCACACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGCTATATACTGGGCGTTGGGTGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-122 (SEQ ID NO: 248)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTGCGAATACTGCTGATCGTAGATACTACGCACACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGATATATACGGGTCGGTGGGCGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-123 (SEQ ID NO: 249)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGAATACTGCTGATCGTAGATACTACGCAGACGCGGTGAAGGGGCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGATATATACGGGTCGTTGGGAGCCTTTTGTCTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-124 (SEQ ID NO: 250)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCGGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGAATACGGGCGATCGTAGATACTACGCACACGCGGTGAAGGGGCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGATATATACGGGTCGTTGGGAGCCTTTTGTCTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-125 (SEQ ID NO: 251)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTGCGAATACTGCTGATCGTAGATACTACGCAGACGCGGTGAAGGGGCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGATATATACGGGTCGTTGGGAGCCTTTTGTCTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-126 (SEQ ID NO: 252)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTGCGAATACGGGTGATCGTAGATACTACGCACACGCGGTGAAGGGGCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGATATATACGGGTCGTTGGGAGCCTTTTGTCTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-127 (SEQ ID NO: 253)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGAATACTGCTGATCGTAGATACTACGCACACGCGGTGAAGGGGCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGATATATACGGGTCGTTGGGAGCCTTTTGTCTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-128 (SEQ ID NO: 254)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTGCGAATACGGCTGATCGTAGATACTACGCACACGCGGTGAAGGGGCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGATATATACGGGTCGTTGGGAGCCTTTTGTCTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-129 (SEQ ID NO: 255)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTGTGAATACGGGTGATCGTAGATACTACGCAGACGCGGTGAAGGGGCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGATATATACGGGTCGTTGGGAGCCTTTTGTCTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-130 (SEQ ID NO: 256)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTGCGAATACGGGTGATCGTAGATACTACGCAGACGCGGTGAAGGGGCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGATATATACGGGTCGTTGGGAGCCTTTTGTCTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-131 (SEQ ID NO: 257)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGGATACTGCTGATCGTACATACTACGATCACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGATATATACGGGTCGGTGGGCGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-132 (SEQ ID NO: 258)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGGATACTGCTGATCGTACATACTACGATCACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGATATATACGGGTCGTTGGAGGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-133 (SEQ ID NO: 259)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGGATACTGCTGATCGTACATACTACGATCACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGATATATACGGGTCGTTGGGAGCCTTTTGTCTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-134 (SEQ ID NO: 260)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGGATACTGCTGATCGTACATACTACTCACACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCTGAGGACACCGCGGTATATTACTGTGCGATATATACTGGGCGTTGGGTGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-135 (SEQ ID NO: 261)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGGATACTGCTGATCGTACATACTACACACACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCTGAGGACACCGCGGTATATTACTGTGCGATATATACTGGGCGTTGGGTGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-137 (SEQ ID NO: 262)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGGATACTGCTGATCGTACATACTACACAGACGCGGTGAAGGGGCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGATATATACGGGTCGTTGGGAGCCTTTTGTCTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-138 (SEQ ID NO: 263)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTTTCAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGGATACTGCTGATCGTACATACTACGCACACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGATATATACGGGTCGGTGGGCGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-139 (SEQ ID NO: 264)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTTTGAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGGATACTGCTGATCGTACATACTACGCACACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGATATATACGGGTCGGTGGGCGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-140 (SEQ ID NO: 265)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTTTCAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTGCGGATACGGGTGATCGTAGATACTACGATGACTCTGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGATATATACGGGTCGTTGGGAGCCTTTTGTCTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-141 (SEQ ID NO: 266)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTTTCAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGGATACTGCTGATCGTAGATACTACGATGACTCTGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGATATATACGGGTCGTTGGGAGCCTTTTGTCTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-142 (SEQ ID NO: 267)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGCCTCTCCTGTGCAGCCTCCGGATTCACCTTTTTCAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGGATACGGGTGATCGTAGATACTACGATCACTCTGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGATATATACGGGTCGTTGGGAACCTTTTGTCTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-143 (SEQ ID NO: 268)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTTTCAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGGATACGGGTGATCGTAGATACTACGATGACGCGGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGATATATACGGGTCGTTGGGAGCCTTTTGTCTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-144 (SEQ ID NO: 269)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTTTCAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTGCGGATACTGCTGATCGTAGATACTACGATGACTCTGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGATATATACGGGTCGTTGGGAGCCTTTTGTCTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-145 (SEQ ID NO: 270)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTTTCAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTGCGGATACGGGTGATCGTAGATACTACGATCACTCTGTGAAGGGCCGGTTCACTATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGATATATACGGGTCGTTGGGAGCCTTTTGTCTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-146 (SEQ ID NO: 271)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTTTCAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTGCGGATACGGGTGATCGTAGATACTACGATGACGCGGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGATATATACGGGTCGTTGGGAGCCTTTTGTCTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-147 (SEQ ID NO: 272)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGGATACTGCTGATCGTACATACTACGCACACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGATATATACGGGTCGTTGGGGGCCTTTTGTCTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-148 (SEQ ID NO: 273)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGGATACTGCTGATCGTACATACTACGCACACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGATATATACGGGTCGTTGGGTGCCTTTTGCCTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-149 (SEQ ID NO: 274)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGGATACTGCTGATCGTACATACTACGCACACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGATATATACGGGTCGTTGGGGACCTTTTCAGTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-150 (SEQ ID NO: 275)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGGATACTGCTGATCGTACATACTACGCACACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGATATATACGGGTCGTTGGGAGCCTTTTCAGTACTGGGGTCAGGGAACTCTGGTCACCGTCTCGAGC >DOM1h-574-151 (SEQ ID NO: 276)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGGATACTGCTGATCGTACATACTACGCACACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGATATATACGGGTCGTTGGGCGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-152 (SEQ ID NO: 277)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGGATACTGCTGATCGTACATACTACGCACACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGATATATACGGGTCGTTGGGCGCCTTTTCAGTACTGGGGTCAGGGAACTCTGGTCACCGTCTCGAGC >DOM1h-574-153 (SEQ ID NO: 278)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGGATACTGCTGATCGTACATACTACGCACACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGATATATACGGGTCGTTGGGTGCCTTTTCAGTACTGGGGTCAGGGCACCCTGGTCACCGTCTCGAGC >DOM1h-574-154 (SEQ ID NO: 279)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGGATACCGGTGATCGTAGATACTACGATCACTCTGTGAAGGGCCGGTTCACTATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGATATATACGGGTCGGTGGGCGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-155 (SEQ ID NO: 280)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTTTGAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGGATACTGCTGATCGTACATACTACGCACACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCTGAGGACACCGCGGTATATTACTGTGCGATATATACTGGGCGTTGGGTGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-156 (SEQ ID NO: 281)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTTTCAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGGATACTGCTGATCGTACATACTACGCACACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCTGAGGACACCGCGGTATATTACTGTGCGATATATACTGGGCGTTGGGTGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-157 (SEQ ID NO: 282)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTTTGAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGGATACTGCTGATCGTACATACTACGATCACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGATATATACGGGTCGTTGGAGGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-158 (SEQ ID NO: 283)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTTTCAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGGATACTGCTGATCGTACATACTACGATCACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGATATATACGGGTCGTTGGAGGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-159 (SEQ ID NO: 284)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTTTCAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGGATACTGCTGATCGTACATACTACGATCACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGATATATACGGGTCGTTGGGAGCCTTTTGTCTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-160 (SEQ ID NO: 285)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTTTGAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGGATACTGCTGATCGTACATACTACGATCACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGATATATACGGGTCGTTGGGAGCCTTTTGTCTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-161 (SEQ ID NO: 286)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTTTGAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGGATACTGCTGATCGTACATACTACTCACACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCTGAGGACACCGCGGTATATTACTGTGCGATATATACTGGGCGTTGGGTGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-162 (SEQ ID NO: 287)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTTTCAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGGATACTGCTGATCGTACATACTACTCACACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCTGAGGACACCGCGGTATATTACTGTGCGATATATACTGGGCGTTGGGTGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-163 (SEQ ID NO: 288)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTTTCAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGGATACTGCTGATCGTACATACTACACACACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCTGAGGACACCGCGGTATATTACTGTGCGATATATACTGGGCGTTGGGTGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-164 (SEQ ID NO: 289)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTTTGAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGGATACTGCTGATCGTACATACTACACACACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCTGAGGACACCGCGGTATATTACTGTGCGATATATACTGGGCGTTGGGTGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-165 (SEQ ID NO: 290)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTTTCAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGGATACTGCTGATCGTACATACTACGCACACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGATATATACGGGTCGTTGGGCGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-166 (SEQ ID NO: 291)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTTTGAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGGATACTGCTGATCGTACATACTACGCACACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGATATATACGGGTCGTTGGGCGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-167 (SEQ ID NO: 292)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTTTGAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGGATACCGGTGATCGTAGATACTACGATCACTCTGTGAAGGGCCGGTTCACTATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGATATATACGGGTCGGTGGGCGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-168 (SEQ ID NO: 293)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTTTCAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGGATACCGGTGATCGTAGATACTACGATCACTCTGTGAAGGGCCGGTTCACTATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGATATATACGGGTCGGTGGGCGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-169 (SEQ ID NO: 294)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTGCGGATACTGCTGATCGTACATACTACGCACACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCTGAGGACACCGCGGTATATTACTGCGCGATATATACTGGGCGTTGGGTGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-170 (SEQ ID NO: 295)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTTTTAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGGATACTGCTGATCGTACATACTACGCACACGCGGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCTGAGGACACCGCGGTATATTACTGTGCGATATATACTGGGCGTTGGGTGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-171 (SEQ ID NO: 296)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTGCAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTGCGGATACTGCTGATCGTACATACTACGATCACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCTGAGGACACCGCGGTATATTACTGTGCGATATATACTGGGCGTTGGGTGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-172 (SEQ ID NO: 297)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTGCGGATACTGCTGATCGTACATACTACGATCACGCGGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCTGAGGACACCGCGGTATATTACTGTGCGATATATACTGGGCGTTGGGTGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-173 (SEQ ID NO: 298)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTGCGGATACTGCTGATCGTAGATACTACGCACACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGATATATACGGGTCGGTGGGCGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-174 (SEQ ID NO: 299)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGGATACTGCTGATCGTAGATACTACGCACACGCGGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGATATATACGGGTCGGTGGGCGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-175 (SEQ ID NO: 300)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTGCGGATACTGCTGATCGTAGATACTACGCACACGCGGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGATATATACGGGTCGGTGGGCGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-176 (SEQ ID NO: 301)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGGATACTGCTGATCGTAGATACTACGATCACGCGGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGATATATACGGGTCGGTGGGCGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-177 (SEQ ID NO: 302)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTGCGGATACTGCTGATCGTAGATACTACGATCACGCGGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGATATATACGGGTCGGTGGGCGCCTTTTGAGTACTGGGGTCAGGGGACCCTGGTCACCGTCTCGAGC >DOM1h-574-178 (SEQ ID NO: 303)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTGTTAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTGCGGATACTGCTGATCGTAGATACTACGATCACTCCGTGAAGGGCCGGTTCACCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGATATATACGGGTCGGTGGGCGCCTTTTGAGTACTGGGGTCAGGGAACCCTGGTCACCGTCTCGAGC >DOM1h-574-179 (SEQ ID NO: 304)GAGGTGCAGCTGCTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTTTCAAGTATTCGATGGGGTGGGTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACAGATTTCGGATACTGCTGATCGTAGATACTACGATGACGCGGTGAAGGGCCGGTTCACCATCACCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCGGTATATTACTGTGCGATATATACGGGTCGTTGGGAGCCTTTTGTCTACTGGGGTCAGGGAACCCTGGTCACC GTCTCGAGC

TABLE 5 Anti-serum albumin dAb (DOM7h) fusions (used in Rat studies):-DOM7h-14/Exendin-4 fusion DMS number 7138 Amino acid sequence (SEQ IDNO: 305) HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPSGGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQWIGSQLSWYQQKPGKAPKLLIMWRSSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCAQGAALPRTFGQGTKVEIKR Nucleotidesequence (SEQ ID NO: 306)CATGGTGAAGGAACATTTACCAGTGACTTGTCAAAACAGATGGAAGAGGAGGCAGTGCGGTTATTTATTGAGTGGCTTAAGAACGGAGGACCAAGTAGCGGGGCACCTCCGCCATCGGGTGGTGGAGGCGGTTCAGGCGGAGGTGGCAGCGGCGGTGGCGGGTCGGACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACCGTGTCACCATCACTTGCCGGGCAAGTCAGTGGATTGGGTCTCAGTTATCTTGGTACCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCATGTGGCGTTCCTCGTTGCAAAGTGGGGTCCCATCACGTTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAACCTGAAGATTTTGCTACGTACTACTGTGCTCAGGGTGCGGCGTTGCCTAGGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAACGG DOM7h-14-10/Exendin-4 fusion DMS number 7139 Amino acidsequence (SEQ ID NO: 307)HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPSGGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQWIGSQLSWYQQKPGKAPKLLIMWRSSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCAQGLRHPKTFGQGTKVEIKR Nucleotidesequence (SEQ ID NO: 308)CATGGTGAAGGAACATTTACCAGTGACTTGTCAAAACAGATGGAAGAGGAGGCAGTGCGGTTATTTATTGAGTGGCTTAAGAACGGAGGACCAAGTAGCGGGGCACCTCCGCCATCGGGTGGTGGAGGCGGTTCAGGCGGAGGTGGCAGCGGCGGTGGCGGGTCGGACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACCGTGTCACCATCACTTGCCGGGCAAGTCAGTGGATTGGGTCTCAGTTATCTTGGTACCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCATGTGGCGTTCCTCGTTGCAAAGTGGGGTCCCATCACGTTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAACCTGAAGATTTTGCTACGTACTACTGTGCTCAGGGTTTGAGGCATCCTAAGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAACGG DOM7h-14-18/Exendin-4 fusion DMS number 7140 Aminoacid sequence (SEQ ID NO: 309)HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPSGGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQWIGSQLSWYQQKPGKAPKLLIMWRSSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCAQGLMKPMTFGQGTKVEIKR Nucleotidesequence (SEQ ID NO: 310)CATGGTGAAGGAACATTTACCAGTGACTTGTCAAAACAGATGGAAGAGGAGGCAGTGCGGTTATTTATTGAGTGGCTTAAGAACGGAGGACCAAGTAGCGGGGCACCTCCGCCATCGGGTGGTGGAGGCGGTTCAGGCGGAGGTGGCAGCGGCGGTGGCGGGTCGGACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACCGTGTCACCATCACTTGCCGGGCAAGTCAGTGGATTGGGTCTCAGTTATCTTGGTACCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCATGTGGCGTTCCTCGTTGCAAAGTGGGGTCCCATCACGTTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAACCTGAAGATTTTGCTACGTACTACTGTGCTCAGGGTCTTATGAAGCCTATGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAACGG DOM7h-14-19/Exendin-4 fusion DMS number 7141 Aminoacid sequence (SEQ ID NO: 311)HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPSGGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTISCRASQWIGSQLSWYQQKPGEAPKLLIMWRSSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCAQGAALPRTFGQGTKVEIKR Nucleotidesequence (SEQ ID NO: 312)CATGGTGAAGGAACATTTACCAGTGACTTGTCAAAACAGATGGAAGAGGAGGCAGTGCGGTTATTTATTGAGTGGCTTAAGAACGGAGGACCAAGTAGCGGGGCACCTCCGCCATCGGGTGGTGGAGGCGGTTCAGGCGGAGGTGGCAGCGGCGGTGGCGGGTCGGACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACCGTGTCACCATCTCTTGCCGGGCAAGTCAGTGGATTGGGTCTCAGTTATCTTGGTACCAGCAGAAACCAGGGGAAGCCCCTAAGCTCCTGATCATGTGGCGTTCCTCGTTGCAAAGTGGGGTCCCATCACGTTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAACCTGAAGATTTTGCTACGTACTACTGTGCTCAGGGTGCGGCGTTGCCTAGGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAACGG DOM7h-11/Exendin-4 fusion DMS number 7142 Amino acidsequence (SEQ ID NO: 313)HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPSGGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASRPIGTTLSWYQQKPGKAPKLLIWFGSRLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCAQAGTHPTTFGQGTKVEIKR Nucleotidesequence (SEQ ID NO: 314)CATGGTGAAGGAACATTTACCAGTGACTTGTCAAAACAGATGGAAGAGGAGGCAGTGCGGTTATTTATTGAGTGGCTTAAGAACGGAGGACCAAGTAGCGGGGCACCTCCGCCATCGGGTGGTGGAGGCGGTTCAGGCGGAGGTGGCAGCGGCGGTGGCGGGTCGGACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACCGTGTCACCATCACTTGCCGGGCAAGTCGTCCGATTGGGACGACGTTAAGTTGGTACCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTGGTTTGGTTCCCGGTTGCAAAGTGGGGTCCCATCACGTTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAACCTGAAGATTTTGCTACGTACTACTGTGCGCAGGCTGGGACGCATCCTACGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAACGG DOM7h-11-12/Exendin-4 fusion DMS number 7147 Aminoacid sequence (SEQ ID NO: 315)HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPSGGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASRPIGTMLSWYQQKPGKAPKLLILFGSRLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCAQAGTHPTTFGQGTKVEIKR Nucleotidesequence (SEQ ID NO: 316)CATGGTGAAGGAACATTTACCAGTGACTTGTCAAAACAGATGGAAGAGGAGGCAGTGCGGTTATTTATTGAGTGGCTTAAGAACGGAGGACCAAGTAGCGGGGCACCTCCGCCATCGGGTGGTGGAGGCGGTTCAGGCGGAGGTGGCAGCGGCGGTGGCGGGTCGGACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACCGTGTCACCATCACTTGCCGGGCAAGTCGTCCGATTGGGACGATGTTAAGTTGGTACCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTTGTTTGGTTCCCGGTTGCAAAGTGGGGTCCCATCACGTTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAACCTGAAGATTTTGCTACGTACTACTGTGCGCAGGCTGGGACGCATCCTACGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAACGG DOM7h-11-15/Exendin-4 fusion DMS number 7143 Aminoacid sequence (SEQ ID NO: 317)HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPSGGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASRPIGTMLSWYQQKPGKAPKLLILAFSRLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCAQAGTHPTTFGQGTKVEIKR Nucleotidesequence (SEQ ID NO: 318)CATGGTGAAGGAACATTTACCAGTGACTTGTCAAAACAGATGGAAGAGGAGGCAGTGCGGTTATTTATTGAGTGGCTTAAGAACGGAGGACCAAGTAGCGGGGCACCTCCGCCATCGGGTGGTGGAGGCGGTTCAGGCGGAGGTGGCAGCGGCGGTGGCGGGTCGGACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACCGTGTCACCATCACTTGCCGGGCAAGTCGTCCGATTGGGACGATGTTAAGTTGGTACCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCCTTGCTTTTTCCCGTTTGCAAAGTGGGGTCCCATCACGTTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAACCTGAAGATTTTGCTACGTACTACTGCGCGCAGGCTGGGACGCATCCTACGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAACGG DOM7h14-10/G4SC-NCE fusion Amino acid sequence (SEQID NO: 319) encoding DOM7h14-10/G4SCDIQMTQSPSSLSASVGDRVTITCRASQWIGSQLSWYQQKPGKAPKLLIMWRSSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCAQGLRHPKTFGQGTKVEIKRGGGGSC TheC-terminal cysteine can be linked to a new chemical entity(pharmaceutical chemical compound, NCE), eg using maleimide linkage.Nucleotide sequence (SEQ ID NO: 320) encoding DOM7h14-10/G4SCGACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACCGTGTCACCATCACTTGCCGGGCAAGTCAGTGGATTGGGTCTCAGTTATCTTGGTACCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCATGTGGCGTTCCTCGTTGCAAAGTGGGGTCCCATCACGTTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAACCTGAAGATTTTGCTACGTACTACTGTGCTCAGGGTTTGAGGCATCCTAAGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAACGGGGTGGCGGAGGGGGTTCCTGT DOM7h14-10/TVAAPSC fusion Amino acidsequence (SEQ ID NO: 321)DIQMTQSPSSLSASVGDRVTITCRASQWIGSQLSWYQQKPGKAPKLLIMWRSSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCAQGLRHPKTFGQGTKVEIKRT VAAPSC TheC-terminal cysteine can be linked to a new chemical entity(pharmaceutical chemical compound, NCE), eg using maleimide linkage.Nucleotide sequence (SEQ ID NO: 322)GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACCGTGTCACCATCACTTGCCGGGCAAGTCAGTGGATTGGGTCTCAGTTATCTTGGTACCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCATGTGGCGTTCCTCGTTGCAAAGTGGGGTCCCATCACGTTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAACCTGAAGATTTTGCTACGTACTACTGTGCTCAGGGTTTGAGGCATCCTAAGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAACGGACCGTCGCTGCTCCATCTTGT (used in mouse studies):-DOM7h-11/DOM1m-21-23 fusion DMS number 5515 Amino acid sequence (SEQ IDNO: 323) EVQLLESGGGLVQPGGSLRLSCAASGFTFNRYSMGWLRQAPGKGLEWVSRIDSYGRGTYYEDPVKGRFSISRDNSKNTLYLQMNSLRAEDTAVYYCAKISQFGSNAFDYWGQGTQVTVSSASTSGPSDIQMTQSPSSLSASVGDRVTITCRASRPIGTTLSWYQQKPGKAPKLLIWFGSRLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCAQAGTHPTTFGQGTKVEIKR Amino acid plus nucleotide plus myc tag sequence (SEQ IDNO: 324) EVQLLESGGGLVQPGGSLRLSCAASGFTFNRYSMGWLRQAPGKGLEWVSRIDSYGRGTYYEDPVKGRFSISRDNSKNTLYLQMNSLRAEDTAVYYCAKISQFGSNAFDYWGQGTQVTVSSASTSGPSDIQMTQSPSSLSASVGDRVTITCRASRPIGTTLSWYQQKPGKAPKLLIWFGSRLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCAQAGTHPTTFGQGTKVEIKRAAAEQKLISEEDLN Nucleotide sequence (SEQ ID NO: 325)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTAATAGGTATAGTATGGGGTGGCTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACGGATTGATTCTTATGGTCGTGGTACATACTACGAAGACCCCGTGAAGGGCCGGTTCAGCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCCGTATATTACTGTGCGAAAATTTCTCAGTTTGGGTCAAATGCGTTTGACTACTGGGGTCAGGGAACCCAGGTCACCGTCTCGAGCGCTAGCACCAGTGGTCCATCGGACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACCGTGTCACCATCACTTGCCGGGCAAGTCGTCCGATTGGGACGACGTTAAGTTGGTACCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTGGTTTGGTTCCCGGTTGCAAAGTGGGGTCCCATCACGTTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAACCTGAAGATTTTGCTACGTACTACTGTGCGCAGGCTGGGACGCATCCTACGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAACGG Nucleotide plus myc tag sequence (SEQID NO: 326) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTAATAGGTATAGTATGGGGTGGCTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACGGATTGATTCTTATGGTCGTGGTACATACTACGAAGACCCCGTGAAGGGCCGGTTCAGCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCCGTATATTACTGTGCGAAAATTTCTCAGTTTGGGTCAAATGCGTTTGACTACTGGGGTCAGGGAACCCAGGTCACCGTCTCGAGCGCTAGCACCAGTGGTCCATCGGACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACCGTGTCACCATCACTTGCCGGGCAAGTCGTCCGATTGGGACGACGTTAAGTTGGTACCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTGGTTTGGTTCCCGGTTGCAAAGTGGGGTCCCATCACGTTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAACCTGAAGATTTTGCTACGTACTACTGTGCGCAGGCTGGGACGCATCCTACGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAACGGGCGGCCGCAGAACAAAAACTCATCTCAGAAGAGGATCTGAATTAA DOM7h-11-12/DOM1m-21-23 fusion DMS number5516 Amino acid sequence (SEQ ID NO: 327)EVQLLESGGGLVQPGGSLRLSCAASGFTFNRYSMGWLRQAPGKGLEWVSRIDSYGRGTYYEDPVKGRFSISRDNSKNTLYLQMNSLRAEDTAVYYCAKISQFGSNAFDYWGQGTQVTVSSASTSGPSDIQMTQSPSSLSASVGDRVTITCRASRPIGTMLSWYQQKPGKAPKLLILFGSRLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCAQAGTHPTTFGQGTKVEIKR Amino acid plus nucleotide plus myc tag sequence(SEQ ID NO: 328) EVQLLESGGGLVQPGGSLRLSCAASGFTFNRYSMGWLRQAPGKGLEWVSRIDSYGRGTYYEDPVKGRFSISRDNSKNTLYLQMNSLRAEDTAVYYCAKISQFGSNAFDYWGQGTQVTVSSASTSGPSDIQMTQSPSSLSASVGDRVTITCRASRPIGTMLSWYQQKPGKAPKLLILFGSRLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCAQAGTHPTTFGQGTKVEIKRAAAEQKLISEEDLN Nucleotide sequence (SEQ ID NO: 329)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTAATAGGTATAGTATGGGGTGGCTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACGGATTGATTCTTATGGTCGTGGTACATACTACGAAGACCCCGTGAAGGGCCGGTTCAGCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCCGTATATTACTGTGCGAAAATTTCTCAGTTTGGGTCAAATGCGTTTGACTACTGGGGTCAGGGAACCCAGGTCACCGTCTCGAGCGCTAGCACCAGTGGTCCATCGGACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACCGTGTCACCATCACTTGCCGGGCAAGTCGTCCGATTGGGACGATGTTAAGTTGGTACCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTTGTTTGGTTCCCGGTTGCAAAGTGGGGTCCCATCACGTTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAACCTGAAGATTTTGCTACGTACTACTGTGCGCAGGCTGGGACGCATCCTACGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAACGG Nucleotide plus myc tag sequence(SEQ ID NO: 330) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTAATAGGTATAGTATGGGGTGGCTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACGGATTGATTCTTATGGTCGTGGTACATACTACGAAGACCCCGTGAAGGGCCGGTTCAGCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCCGTATATTACTGTGCGAAAATTTCTCAGTTTGGGTCAAATGCGTTTGACTACTGGGGTCAGGGAACCCAGGTCACCGTCTCGAGCGCTAGCACCAGTGGTCCATCGGACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACCGTGTCACCATCACTTGCCGGGCAAGTCGTCCGATTGGGACGATGTTAAGTTGGTACCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTTGTTTGGTTCCCGGTTGCAAAGTGGGGTCCCATCACGTTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAACCTGAAGATTTTGCTACGTACTACTGTGCGCAGGCTGGGACGCATCCTACGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAACGGGCGGCCGCAGAACAAAAACTCATCTCAGAAGAGGATCTGAATTAA DOM7h-11-15/DOM1m-21-23 fusion DMSnumber 5517 Amino acid sequence (SEQ ID NO: 331)EVQLLESGGGLVQPGGSLRLSCAASGFTFNRYSMGWLRQAPGKGLEWVSRIDSYGRGTYYEDPVKGRFSISRDNSKNTLYLQMNSLRAEDTAVYYCAKISQFGSNAFDYWGQGTQVTVSSASTSGPSDIQMTQSPSSLSASVGDRVTITCRASRPIGTMLSWYQQKPGKAPKLLILAFSRLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCAQAGTHPTTFGQGTKVEIKR Amino acid plus nucleotide plus myc tag sequence(SEQID NO: 332) EVQLLESGGGLVQPGGSLRLSCAASGFTFNRYSMGWLRQAPGKGLEWVSRIDSYGRGTYYEDPVKGRFSISRDNSKNTLYLQMNSLRAEDTAVYYCAKISQFGSNAFDYWGQGTQVTVSSASTSGPSDIQMTQSPSSLSASVGDRVTITCRASRPIGTMLSWYQQKPGKAPKLLILAFSRLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCAQAGTHPTTFGQGTKVEIKRAAAEQKLISEEDLN Nucleotide sequence (SEQ ID NO: 333)GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTAATAGGTATAGTATGGGGTGGCTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACGGATTGATTCTTATGGTCGTGGTACATACTACGAAGACCCCGTGAAGGGCCGGTTCAGCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCCGTATATTACTGTGCGAAAATTTCTCAGTTTGGGTCAAATGCGTTTGACTACTGGGGTCAGGGAACCCAGGTCACCGTCTCGAGCGCTAGCACCAGTGGTCCATCGGACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACCGTGTCACCATCACTTGCCGGGCAAGTCGTCCGATTGGGACGATGTTAAGTTGGTACCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCCTTGCTTTTTCCCGTTTGCAAAGTGGGGTCCCATCACGTTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAACCTGAAGATTTTGCTACGTACTACTGCGCGCAGGCTGGGACGCATCCTACGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAACGG Nucleotide plus myc tag sequence(SEQ ID NO: 334) GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGCGTCTCTCCTGTGCAGCCTCCGGATTCACCTTTAATAGGTATAGTATGGGGTGGCTCCGCCAGGCTCCAGGGAAGGGTCTAGAGTGGGTCTCACGGATTGATTCTTATGGTCGTGGTACATACTACGAAGACCCCGTGAAGGGCCGGTTCAGCATCTCCCGCGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGTGCCGAGGACACCGCCGTATATTACTGTGCGAAAATTTCTCAGTTTGGGTCAAATGCGTTTGACTACTGGGGTCAGGGAACCCAGGTCACCGTCTCGAGCGCTAGCACCAGTGGTCCATCGGACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACCGTGTCACCATCACTTGCCGGGCAAGTCGTCCGATTGGGACGATGTTAAGTTGGTACCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCCTTGCTTTTTCCCGTTTGCAAAGTGGGGTCCCATCACGTTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAACCTGAAGATTTTGCTACGTACTACTGCGCGCAGGCTGGGACGCATCCTACGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAACGGGCGGCCGCAGAACAAAAACTCATCTCAGAAGAGGATCTGAATTAA

Where a myc-tagged molecule is indicated in this table, this was theversion used in PK studies in the examples. Where no myc-taggedsequences are given, the PK studies in the examples were not done withmyc-tagged material, ie, the studies were done with the non-taggedconstructs shown.

EXEMPLIFICATION

All numbering in the experimental section is according to Kabat (Kabat,E. A. National Institutes of Health (US) & Columbia University.Sequences of proteins of immunological interst, edn 5 (US Dept. OfHealth and Human Services Public Health Service, National Institues ofHealth, Bethesda, Md., 1991)).

Derivation of DOM7h-11 and DOM7h-14 variants is described. DOM7h-14variants are not according to the invention.

Example 1 Vk Affinity Maturation Selections:

HSA (Human Serum Albumin) and RSA (Rat Serum Albumin) antigens wereobtained from Sigma (essentially fatty acid free, ˜99% (agarose gelelectrophoresis), lyophilized powder Cat. No. A3782 and A6414respectively)

Biotinylated products of above two antigens were made by using EZ LinkSulfo-NHS—SS-Biotin (Pierce, Cat. No. 21331). Free biotin reagent wasremoved by passing the samples twice through PD10 desalting columnfollowed by overnight dialysis against 1000× excess volume of PBS at 4°C. Resulting product was tested by mass spec and 1-2 biotins permolecule were observed.

Affinity Maturation Libraries:

Both error-prone and CDR libraries were created using DOM7h-11 andDOM7h-14 parental dAbs (see WO2008/096158 for the sequences of DOM7h-11and DOM7h-14). The CDR libraries were generated in the pDOM4 vector andthe error prone libraries were generated in the pDOM33 vector (to allowfor selection with or without protease treatment). Vector pDOM4, is aderivative of the Fd phage vector in which the gene III signal peptidesequence is replaced with the yeast glycolipid anchored surface protein(GAS) signal peptide. It also contains a c-myc tag between the leadersequence and gene III, which puts the gene III back in frame. Thisleader sequence functions well both in phage display vectors but also inother prokaryotic expression vectors and can be universally used. pDOM33is a modified version of the pDOM4 vector where the c-myc tag has beenremoved which renders the dAb-phage fusion resistant to the proteasetrypsin. This allows the use of trypsin within the phage selection toselect for dAbs that are more protease stable (see WO2008149143).

For error-prone maturation libraries, plasmid DNA encoding the dAb to bematured was amplified by PCR, using the GENEMORPH® II RANDOM MUTAGENESISKIT (random, unique mutagenesis kit, Stratagene). The product wasdigested with SalI and Not I and used in a ligation reaction with cutphage vector pDOM33.

For the CDR libraries, PCR reactions were performed using degenerateoligonucleotides containing NNK or NNS codons to diversify the requiredpositions in the dAb to be affinity matured. Assembly PCR was then usedto generate a full length diversified insert. The insert was digestedwith Sal I and Not I and used in a ligation reaction with pDOM4 formutagenesis of multiple residues and pDOM5 for mutagenesis of singleresidues. The pDOM5 vector is a pUC119-based expression vector whereprotein expression is driven by the LacZ promoter. A GAS1 leadersequence (see WO 2005/093074) ensures secretion of isolated, solubledAbs into the periplasm and culture supernatant of E. coli. dAbs arecloned SalI/NotI in this vector, which appends a myc tag at theC-terminus of the dAb. This protocol using SalI and Not I results ininclusion of an ST amino acid sequence at the N-terminus.

The ligation produced by either method was then used to transform E.coli strain TB1 by electroporation and the transformed cells plated on2×TY agar containing 15 μg/ml tetracycline, yielding library sizes of>5×10⁷ clones.

The error-prone libraries had the following average mutation rate andsize: DOM7h-11 (2.5 mutations per dAb), size:6.1×10⁸, DOM7h-14 (2.9mutations per dAb), size:5.4×10⁸.

Each CDR library has four amino acid diversity. Two libraries weregenerated for each of CDRs 1 and 3, and one library for CDR2. Thepositions diversified within each library are as follows (amino acidsbased on VK dummy DPK9 sequence):

Library size DOM7h-11 DOM7h-14 1-Q27, S28, S30, S31 (CDR1) 8.8 × 10⁷ 5.8× 10⁷ 2-S30, S31, Y32, N34 (CDR1) 4.6 × 10⁸ 4.2 × 10⁸ 3-Y49, A50, A51,S53 (CDR2) 3.9 × 10⁸ 2.4 × 10⁸ 4-Q89, S91, Y92, S93 (CDR3) 1.8 × 10⁸ 2.5× 10⁸ 5-Y92, Y93, T94, N96 (CDR3) 4.0 × 10⁸ 3.3 × 10⁸

Example 2 Selection Strategies

Three phage selection strategies were adopted for Vκ AlbudAb™(anti-serum albumin dAb) affinity maturation:

-   -   1) Selections against HSA only:    -   Three rounds of selection against HSA were carried out. The        error prone libraries and each CDR library were selected as an        individual pool in all rounds. The first round of selection was        performed against HSA passively coated onto an immunotube at 1        mg/ml. Round 2 was performed against 100 nM HSA and round 3        against 10 nM (CDR selections) or 20 or 100 nM (Error prone        selections) HSA, both as soluble selections followed by a fourth        round of selection with the error prone libraries against 1.5 nM        HSA as a soluble selection. The error prone libraries were        eluted with 0.1M glycine pH 2.0 before neutralisation with 1M        Tris pH 8.0 and the CDR libraries were eluted with 1 mg/ml        trypsin before infection into log phase TG1 cells. The third        round of each selection was subcloned into pDOM5 for screening.        Soluble selections used biotinylated HSA.    -   2) Trypsin selections against HSA:    -   In order to select dAbs with increased protease resistance        compared to the parental clone and with potentially improved        biophysical properties, trypsin was used in phage selections        (see WO2008149143). Four rounds of selection were preformed        against HSA. The first round of selection of error prone        libraries was performed against passively coated HSA at 1 mg/ml        without trypsin; the second round against passively coated HSA        at 1 mg/ml with 20 μg/mltrypsin for 1 hour at 37° C.; the third        round selection was performed by soluble selection using        biotinylated HSA against 100 nM HSA with 20 μg/ml or 100        μg/mltrypsin for 1 hour at 37° C. The final round of selection        was performed by soluble selection using biotinylated HSA        against 100 nM HSA with 100 μg/mltrypsin overnight at 37° C.    -   3) Cross-over selections against HSA (round 1) and RSA (rounds        2-4):    -   The first round selection was carried out against 1 mg/ml        passively coated HSA or 1 μM HSA (soluble selection), followed        by a further three rounds of soluble selections against        biotinylated RSA at concentrations of 1 μM for round 1, 100 nm        for round 2 and 20 nM, 10 nM or 1 nM for round 3.

Screening Strategy and Affinity Determination:

In each case after selection a pool of phage DNA from the appropriateround of selection is prepared using a QIAfilter midiprep kit (Qiagen),the DNA is digested using the restriction enzymes SalI and NotI and theenriched V genes are ligated into the corresponding sites in pDOM5 thesoluble expression vector which expresses the dAb with a myc tag (seePCT/EP2008/067789). The ligated DNA is used to electro-transform E. coliHB 2151 cells which are then grown overnight on agar plates containingthe antibiotic carbenicillin. The resulting colonies are individuallyassessed for antigen binding. In each case at least 96 clones weretested for binding to HSA, CSA (Cynomlgus monkey Serum Albumin), MSA(mouse serum albumin) and RSA by BIAcore™ (surface plasmon resonance).MSA antigen was obtained from Sigma (essentially fatty acid free, ˜99%(agarose gel electrophoresis), lyophilized powder Cat. No. A3559) andCSA was purified from Cynomolgus serum albumin using prometic blue resin(Amersham). Soluble dAb fragments were produced in bacterial culture inONEX culture media (Novagen) overnight at 37° C. in 96 well plates. Theculture supernatant containing soluble dAb was centrifuged and analysedby BIAcore for binding to high density HSA, CSA, MSA and RSA CM5 chips.Clones were found to bind to all these species of serum albumin byoff-rate screening. The clones were sequenced revealing unique dAbsequences.

The minimum identity to parent (at the amino acid level) of the clonesselected was 97.2% (DOM7h-11-3: 97.2%, DOM7h-11-12: 98.2%, DOM7h11-15:96.3%, DOM7h-11-18: 98.2%, DOM7h-11-19: 97.2%)

The minimum identity to parent (at the amino acid level) of the clonesselected was 96.3% (DOM7h-14-10: 96.3%, DOM7h-14-18: 96.3%, DOM7h-14-19:98.2%, DOM7h-14-28: 99.1%, DOM7h-14-36: 97.2%)

Unique dAbs were expressed as bacterial supernatants in 2.5 L shakeflasks in Onex media at 30° C. for 48 hrs at 250 rpm. dAbs were purifiedfrom the culture media by absorption to protein L agarose followed byelution with 10 mM glycine pH2.0. Binding to HSA, CSA, MSA and RSA byBIAcore was confirmed using purified protein at 3 concentrations 1 μM,500 nM and 50 nM. To determine the binding affinity (K_(D)) of theAlbudAbs to each serum albumin; purified dAbs were analysed by BIAcoreover albumin concentration range from 5000 nM to 39 nM (5000 nM, 2500nM, 1250 nM, 625 nM, 312 nM, 156 nM, 78 nM, 39 nM).

TABLE 6 Affinity (K_(D)) AlbudAb to SA (nM) Kd Ka Rat DOM7h-14 602.095E−01 4.00E+06 DOM7h-14-10 4 9.640E−03 4.57E+06 DOM7h-14-18 4102.275E−01 5.60E+05 DOM7h-14-19 890 2.870E−01 3.20E+05 DOM7h-14-28 45(140) 7.0E−02 2.10E+06 (1.141e−1) (8.3e5) DOM7h-14-36 30 (6120) 2.9E−021.55E+06 (5.54e−2) (9e3) DOM7h-11 2100 1.00E−01 4.80E+04 DOM7h-11-310000 (88000) (7.18e−1) (8.11e3) DOM7h-11-12 200 5.22E−01 2.76E+06DOM7h-11-15 20 2.10E−02 1.10E+06 DOM7h-11-18 80 (29000) 6.0E−02 1.64E+06(3.7e−1) (1.3e4) DOM7h-11-19 28 (17000) 9.1e−02 9.80E+05 (1.4c-1)(8.1c3) Cyno DOM7h-14 66 9.65E−02 1.50E+06 DOM7h-14-10 9 1.15E−021.60E+06 DOM7h-14-18 180 1.05E−01 6.30E+5 DOM7h-14-19 225 1.56E−017.00E+05 DOM7h-14-28 66 (136) 1.3E−01 2.50E+06 (1.34e−1) (9.8e5)DOM7h-14-36 35 (7830) 1.9E−02 9.80E+06 (1.1e−1) (1.43e4) DOM7h-11 10006.82E−01 8.00E+05 DOM7h-11-3 670 (200) 9.6E−02 2.90E+05 (1.5e−1)(7.26e5) DOM7h-11-12 ≧6000 DOM7h-11-15 3 5.57E−03 5.80E+06 DOM7h-11-1810000 (65000) 1.36 2.25E+05 (4.8e−1) (7.3e3) DOM7h-11-19 ≧10000 (375000)(6.2e−1) (1.7e3) Mouse DOM7h-14 12 4.82E−02 4.10E+06 DOM7h-14-10 303.41E−02 1.29E+06 DOM7h-14-18 65 9.24E−02 2.28E+06 DOM7h-14-19 605.76E−02 1.16E+06 DOM7h-14-28 26 (31) 3.4E−02 1.60E+06 (7.15e−2)(2.28e6) DOM7h-14-36 35 (33) 2.3E−02 8.70E+05 (7.06e−2) (2.11e6)DOM7h-11 5000 9.00E−01 DOM7h-11-3 ≧10000 (36000) (6.12e−1) (1.67e4)DOM7h-11-12 130 1.89E−01 1.53E+06 DOM7h-11-15 10 9.40E−03 1.10E+06DOM7h-11-18 150 (1600) 2.4E−02 4.40E+05 (6.23e−2) (4e4) DOM7h-11-19 100(18000) 3.7E−02 1.40E+06 (8.8e−2) (4.9e3) Human DOM7h-14 33 4.17E−021.43E+06 DOM7h-14-10 12 1.39E−02 1.50E+06 DOM7h-14-18 280 3.39E−021.89E+05 DOM7h-14-19 70 5.25E−02 8.26E+05 DOM7h-14-28 30 (8260) 3.3E−021.24E+06 (5.6e−2) (6.78e3) DOM7h-14-36 28 (1260) 2.4E−02 1.23E+06(6.7e−2) (5.4e4) DOM7h-11 2800 6.41E−01 7.00E+05 DOM7h-11-3 32 (130)1.6E−02 6.50E+05 (2.35e−2) (1.86e5) DOM7h-11-12 350 4.13E−01 1.26E+06DOM7h-11-15 1 1.84E−03 2.00E+06 DOM7h-11-18 36 (32000) 5.1E−02 3.40E+06(2.7e−1) (8.39e3) DOM7h-11-19 65 (38000) 1.1E−01 1.80E+06 (2.09e−1)(5.4e3) *: values in brackets were derived from a second, independentSPR experiment.

All DOM7h-14 derived variants are cross-reactive to mouse, rat, humanand cyno serum albumin. DOM7h-14-10 has improved affinity to rat, cynoand human serum albumin compared to parent. DOM7h-14-28 has an improvedaffinity to RSA. DOM7h-14-36 has an improved affinity to RSA, CSA andMSA.

DOM7h-11-3 has improved affinity to CSA and HSA. DOM7h-11-12 hasimproved affinity to RSA, MSA and HSA. DOM7h-11-15 has improved affinityto RSA, MSA, CSA and HSA. DOM7h-11-18 and DOM7h-11-19 have improvedaffinity to RSA, MSA and HSA.

Example 3 Origins of Key DOM7h-11 Lineage Clones

DOM7h-11-3: From affinity maturation performed against HSA using theCDR2 library (Y49, A50, A51, S53), round 3 output 10 nM HSA

DOM7h-11-12: From affinity maturation performed against HSA using theerror prone library, round 3 outputs (100 nM, HSA) with 100 ug/mltrypsin.

DOM7h-11-15: From cross-over selections performed against HSA as round 1followed by additional 3 rounds of selections against RSA using the CDR2library (Y49, A50, A51, S53) at round 3 selection with 1 nM of RSA.

DOM7h-11-18 From cross-over selections performed against HSA as round 1followed by additional 3 rounds of selections against RSA using theerror prone library, round 3 output at 20 nM of RSA

DOM7h-11-19 From cross-over selections performed against HSA as round 1followed by additional 3 rounds of selections against RSA using theerror prone library, round 3 output at 5 nM of RSA

TABLE 7 CDR sequences (according to Kabat; ref. as above) CDR AlbudAbCDR1 CDR2 CDR3 DPK9 Vk dummy SQSISSYLN YAASSLQS QQSYSTPNT (SEQ ID NO:335) (SEQ ID NO: 336) (SEQ ID NO: 337) DOM7h-11 SRPIGTTLS WFGSRLQSAQAGTHPTT (SEQ ID NO: 338) (SEQ ID NO: 339) (SEQ ID NO: 340) DOM7h-11-12SRPIGTMLS LFGSRLQS AQAGTHPTT (SEQ ID NO: 341) (SEQ ID NO: 342) (SEQ IDNO: 343) DOM 7h-11-15 SRPIGTMLS LAFSRLQS AQAGTHPTT (SEQ ID NO: 344) (SEQID NO: 345) (SEQ ID NO: 346) DOM 7h-11-18 SRPIGTMLS WFGSRLQS AQAGTHPTT(SEQ ID NO: 347) (SEQ ID NO: 348) (SEQ ID NO: 349) DOM 7h-11-19SRPIGTMLS LFGSRLQS AQTGTHPTT (SEQ ID NO: 350) (SEQ ID NO: 351) (SEQ IDNO: 352) DOM 7h-11-3 SRPIGTTLS LWFSRLQS AQAGTHPTT (SEQ ID NO: 353) (SEQID NO: 354) (SEQ ID NO: 355)

Example 4 Origins of Key DOM7h-14 Lineage Clones

DOM7h-14-19: From affinity maturation performed against HSA using theerror prone library, round 3 outputs (100 nM, HSA) with 100 ug/mltrypsin.

DOM7h-14-10, DOM7h-14-18, DOM7h-14-28, DOM7h-14-36: From affinitymaturation performed against HSA using CDR3 library (Y92, Y93, T94,N96), round 3 output.

TABLE 8 CDR sequences (according to Kabat; ref. as above) CDR AlbudAbCDR1 CDR2 CDR3 DPK9 Vk dummy SQSISSYLN YAASSLQS QQSYSTPNT (SEQ ID NO:335) (SEQ ID NO: 336) (SEQ ID NO: 337) DOM 7h-14 SQWIGSQLS MWRSSLQSAQGAALPRT (SEQ ID NO: 356) (SEQ ID NO: 357) (SEQ ID NO: 358) DOM7h-14-10 SQWIGSQLS MWRSSLQS AQGLRHPKT (SEQ ID NO: 359) (SEQ ID NO: 360)(SEQ ID NO: 361) DOM 7h-14-18 SQWIGSQLS MWRSSLQS AQGLMKPMT (SEQ ID NO:362) (SEQ ID NO: 363) (SEQ ID NO: 364) DOM 7h-14-19 SQWIGSQLS MWRSSLQSAQGAALPRT (SEQ ID NO: 365) (SEQ ID NO: 366) (SEQ ID NO: 367) DOM7h-14-28 SQWIGSQLS MWRSSLQS AQGAALPKT (SEQ ID NO: 368) (SEQ ID NO: 369)(SEQ ID NO: 370) DOM 7h-14-36 SQWIGSQLS MWRSSLQS AQGFKKPRT (SEQ ID NO:371) (SEQ ID NO: 372) (SEQ ID NO: 373)

Example 5 Expression and Biophysical Characterisation

The routine bacterial expression level in 2.5 L shake flasks wasdetermined following culture in Onex media at 30° C. for 48 hrs at 250rpm. The biophysical characteristics were determined by SEC MALLS andDSC.

SEC MALLS (size exclusion chromatography withmulti-angle-LASER-light-scattering) is a non-invasive technique for thecharacterizing of macromolecules in solution. Briefly, proteins (atconcentration of 1 mg/mL in buffer Dulbecco's PBS at 0.5 ml/min areseparated according to their hydrodynamic properties by size exclusionchromatography (column: TSK3000 from TOSOH Biosciences; S200 fromPharmacia). Following separation, the propensity of the protein toscatter light is measured using a multi-angle-LASER-light-scattering(MALLS) detector. The intensity of the scattered light while proteinpasses through the detector is measured as a function of angle. Thismeasurement taken together with the protein concentration determinedusing the refractive index (R1) detector allows calculation of the molarmass using appropriate equations (integral part of the analysis softwareAstra v.5.3.4.12).

DSC (Differential Scanning calorimetry): briefly, the protein is heatedat a constant rate of 180° C./hrs (at 1 mg/mL in PBS) and a detectableheat change associated with thermal denaturation measured. Thetransition midpoint (_(app)T_(m)) is determined, which is described asthe temperature where 50% of the protein is in its native conformationand the other 50% is denatured. Here, DSC determined the apparenttransition midpoint (appTm) as most of the proteins examined do notfully refold. The higher the Tm, the more stable the molecule. Unfoldingcurves were analysed by non-2-state equations. The software package usedwas Origin^(R) v7.0383.

TABLE 9 Biophysical parameters AlbudAb SEC MALLS DSC Tm(° C.) DOM7h-14 M60   DOM7h-14-10 M 59   DOM7h-14-18 M 58   DOM7h-14-19 M 59  DOM7h-14-28 M 58.3/60.2 DOM7h-14-36 M 59.2 DOM7h-11 M 66.9-72.2DOM7h-11-3 M (95%)* 66.6/70.5 DOM7h-11-12 M (<2% D) 71.7 DOM7h-11-15 M(<5% D) 58.5-60.5 DOM7h-11-18 M (98%) 58.9/65.8 DOM7h-11-19 M 71.8/76.6*in one other trial, monomer was primarily seen by SEC MALLS, althoughlower than 95%

We observed expression levels for all clones in Table 9 in the rangefrom 15 to 119 mg/L in E. coli.

For DOM7h-14 and DOM7h-11 variants, favorable biophysical parameters(monomeric in solution as determined by SEC MALLs and appTm of >55° C.as determined by DSC) and expression levels were maintained duringaffinity maturation. Monomeric state is advantageous because it avoidsdimerisation and the risk of products that may cross-link targets suchas cell-surface receptors.

Example 6 Determination of Serum Half Life in Rat, Mouse and CvnomolgusMonkey

AlbudAbs DOM7h-14-10, DOM7h-14-18, DOM7h-14-19, DOM7h-11, DOM7h11-12 andDOM7h-11-15 were cloned into the pDOM5 vector. For each AlbudAb™, 20-50mg quantities were expressed in E. coli and purified from bacterialculture supernatant using protein L affinity resin and eluted with 100mM glycine pH2. The proteins were concentred to greater than 1 mg/ml,buffer exchanged into PBS and endotoxin depleted using Q spin columns(Vivascience). For Rat pharmacokinetic (PK) analysis, AlbudAbs weredosed as single i.v injections at 2.5 mg/kg using 3 rats per compound.Serum samples were taken at 0.16, 1, 4, 12, 24, 48, 72, 120, 168 hrs.Analysis of serum levels was by anti-myc ELISA as per the methoddescribed below.

For Mouse PK, DOM7h-11, DOM7h11-12 and DOM7h-11-15 were dosed as singlei.v injections at 2.5 mg/kg per dose group of 3 subjects and serumsamples taken at 10 mins; 1 h; 8h; 24h; 48h; 72h; 96h. Analysis of serumlevels was by anti-myc ELISA as per the method described below.

For Cynomolgus monkey PK DOM7h-14-10 and DOM7h-11-15 were dosed assingle i.v injections at 2.5 mg/kg into 3 female Cynomolgus monkeys perdose group and serum samples taken at 0.083, 0.25, 0.5, 1, 2, 4, 8, 24,48, 96, 144, 192, 288, 336, 504 hrs. Analysis of serum levels was byanti-myc ELISA as per the method described below.

Anti-myc ELISA Method

The AlbudAb concentration in serum was measured by anti-myc ELISA.Briefly, goat anti-myc polyclonal antibody (1:500; Abcam, cataloguenumber ab9132) was coated overnight onto Nunc 96-well Maxisorp platesand blocked with 5% BSA/PBS+1% tween. Serum samples were added at arange of dilutions alongside a standard at known concentrations. Boundmyc-tagged AlbudAb was then detected using a rabbit polyclonal anti-Vk(1:1000; in-house reagent, bleeds were pooled and protein A purifiedbefore use) followed by an anti-rabbit IgG HRP antibody (1:10,000;Sigma, catalogue number A2074). Plates were washed between each stage ofthe assay with 3×PBS+0.1% Tween20 followed by 3×PBS. TMB (SureBlue TMB1-Component Microwell Peroxidase Substrate, KPL, catalogue number52-00-00) was added after the last wash and was allowed to develop. Thiswas stopped with 1M HCl and the signal was then measured usingabsorbance at 450 nm.

From the raw ELISA data, the concentration of unknown samples wasestablished by interpolation against the standard curve taking intoaccount dilution factors. The mean concentration result from each timepoint was determined from replicate values and entered into WinNonLinanalysis package (eg version 5.1 (available from Pharsight Corp.,Mountain View, Calif. 94040, USA). The data was fitted using anon-compartmental model, where PK parameters were estimated by thesoftware to give terminal half-lives. Dosing information and time pointswere selected to reflect the terminal phase of each PK profile.

TABLE 10 Single AlbudAb ™ PK PK parameters Albumin AUC CL t½ Vz SpeciesAlbudAb K_(D) (nM) h × μg/ml ml/h/kg h ml/kg Rat DOM7h-14* 60DOM7h-14-10 4 2134.6 1.2 42.1 71.2 DOM7h-14-18 410 617.3 4.1 38.4 228.1DOM 7h-14-19 890 632.6 4.1 36.3 213.3 DOM 7h-11 2100 320.1 7.8 23.3263.9 DOM 7h-11-12 200 398.7 6.4 35.5 321.2 DOM 7h-11-15 20 843.4 3.030.3 130.7 mouse DOM 7h-11 5000 304.7 8.2 18.3 216.8 DOM 7h-11-12 130646.6 3.9 43.9 244.8 DOM 7h-11-15 10 499.2 5.0 33.7 243.4 Cyno DOM7h-14* 66 217.5 DOM 7h-14-10 9 6174.6 0.4 200.8 117.8 DOM 7h-11* 3300135.1 DOM 7h-11-15 3 4195 0.6 198.1 170.3 *Historical data

Pharmacokinetic parameters derived from rat, mouse and cynomolgus monkeystudies were fitted using a non-compartmental model. Key: AUC: Areaunder the curve from dosing time extrapolated to infinity; CL:clearance; t½: is the time during which the blood concentration ishalved; Vz: volume of distribution based on the terminal phase.

DOM7h-11 12 and DOM7h-11-15 have an improved AUC and t½ in rat and mousecompared to parent. DOM7h-11-15 also has an improved AUC and t½ in cynocompared to parent. This improvement in AUC/t½ correlates with animproved in vitro KD to serum albumin.

Example 7 AlbudAb™ IFN Fusions Cloning and Expression

As well as single AlbudAbs, the affinity matured Vk Albudabs were linkedto Interferon alpha 2b (IFNα2b) to determine whether a useful PK of theAlbudAb was maintained as a fusion protein.

Interferon Alpha 2b Amino Acid Sequence:

(SEQ ID NO: 374) CDLPQTHSLGSRRTLMLLAQMRRISLFSCLKDRHDFGFPQEEFGNQFQKAETIPVLHEMIQQIFNLFSTKDSSAAWDETLLDKFYTELYQQLNDLEACVIQGVGVTETPLMKEDSILAVRKYFQRITLYLKEKKYSPCAWEVVRAEIMRS FSLSTNLQESLRSKE

Interferon Alpha 2b Nucleotide Sequence:

(SEQ ID NO: 375) TGTGATCTGCCTCAAACCCACAGCCTGGGTAGCAGGAGGACCTTGATGCTCCTGGCACAGATGAGGAGAATCTCTCTTTTCTCCTGCTTGAAGGACAGACATGACTTTGGATTTCCCCAGGAGGAGTTTGGCAACCAGTTCCAAAAGGCTGAAACCATCCCTGTCCTCCATGAGATGATCCAGCAGATCTTCAATCTCTTCAGCACAAAGGACTCATCTGCTGCTTGGGATGAGACCCTCCTAGACAAATTCTACACTGAACTCTACCAGCAGCTGAATGACCTGGAAGCCTGTGTGATACAGGGGGTGGGGGTGACAGAGACTCCCCTGATGAAGGAGGACTCCATTCTGGCTGTGAGGAAATACTTCCAAAGAATCACTCTCTATCTGAAAGAGAAGAAATACAGCCCTTGTGCCTGGGAGGTTGTCAGAGCAGAAATCATGAGATCTTTTTCTTTGTCAACAAACTTGCAAGAAAGTTTAAGAAGTAAGGAA

IFNα2b was linked to the AlbudAb via a TVAAPS linker region (seeWO2007085814). The constructs were cloned by SOE-PCR (single overlapextension according to the method of Horton et al. Gene, 77, p 61(1989)). PCR amplification of the AlbudAb and IFN sequences were carriedout separately using primers with a ˜15 base pair overlap at the TVAAPSlinker region. The primers used are as follows: —

IFNα2b SOE fragment 5′ (SEQ ID NO: 376) GCCCGGATCCACCGGCTGTGATCTG IFNα2bSOE fragment 3′ (SEQ ID NO: 377) GGAGGATGGAGACTGGGTCATCTGGATGTC Vk SOEfragment 5′ (SEQ ID NO: 378) GACATCCAGATGACCCAGTCTCCATCCTCC Vk SOEfragment 3′ to also introduce a myc tag (SEQ ID NO: 379)GCGCAAGCTTTTATTAATTCAGATCCTCTTCTGAGATGAGTTTTTGTTCTGCGGCCGCCCGTTTGATTTCCACCTTGGTCCC

The fragments were purified separately and subsequently assembled in aSOE (single overlap extension PCR extension) reaction using only theflanking primers.

IFNα2b SOE fragment 5′ (SEQ ID NO: 380) GCCCGGATCCACCGGCTGTGATCTG Vk SOEfragment 3′ to also introduce a myc tag (SEQ ID NO: 381)GCGCAAGCTTTTATTAATTCAGATCCTCTTCTGAGATGAGTTTTTGTTCTGCGGCCGCCCGTTTGATTTCCACCTTGGTCCC

The assembled PCR product was digested using the restriction enzymesBamHI and HindIII and the gene ligated into the corresponding sites inthe pDOM50, a mammalian expression vector which is a pTT5 derivativewith an N-terminal V-J2-C mouse IgG secretory leader sequence tofacilitate expression into the cell media.

Leader Sequence (Amino Acid):

METDTLLLWVLLLWVPGSTG (SEQ ID NO: 382)

Leader Sequence (Nucleotide):

(SEQ ID NO: 383) ATGGAGACCGACACCCTGCTGCTGTGGGTGCTGCTGCTGTGGGTGCCCGGATCCACCGGGC

Plasmid DNA was prepared using QIAfilter megaprep (Qiagen). 1 μg DNA/mlwas transfected with 293-Fectin into HEK293E cells and grown in serumfree media. The protein is expressed in culture for 5 days and purifiedfrom culture supernatant using protein L affinity resin and eluted with100 mM glycine pH2. The proteins were concentred to greater than 1mg/ml, buffer exchanged into PBS and endotoxin depleted using Q spincolumns (Vivascience).

TABLE 11 Interferon alpha 2b-AlbudAb sequences with and without myc-tag(as amino acid- and nucleotide sequence) The Interferon alpha 2b isN-terminal to the AlbudAb in the following fusions. aa + myc nt + myc aano tag nt no tag DMS7321 CDLPQTHSLGSRRT TGCGACTTGCC CDLPQTHSLGTGCGACTTGCC (IFNα2b- LMLLAQMRRISLFS ACAGACACAT SRRTLMLLA ACAGACACATDOM7h- CLKDRHDFGFPQE AGTTTGGGATC QMRRISLFSC AGTTTGGGATC 14)EFGNQFQKAETIPV AAGAAGAACA LKDRHDFGFP AAGAAGAACA LHEMIQQIFNLFSTTTGATGTTATT QEEFGNQFQ TTGATGTTATT KDSSAAWDETLLD AGCACAAATG KAETIPVLHEAGCACAAATG KFYTELYQQLNDL CGTAGAATTTC MIQQIFNLFS CGTAGAATTTCEACVIQGVGVTETP TTTGTTCTCTT TKDSSAAWD TTTGTTCTCTT LMKEDSILAVRKYGTCTAAAGGAC ETLLDKFYTE GTCTAAAGGA FQRITLYLKEKKYS CGTCACGACTT LYQQLNDLECCGTCACGACT PCAWEVVRAEIMR CGGATTCCCTC ACVIQGVGV TCGGATTCCCTSFSLSTNLQESLRS AGGAAGAGTTT TETPLMKEDS CAGGAAGAGT KETVAAPSDIQMTGGAAACCAATT ILAVRKYFQR TTGGAAACCA QSPSSLSASVGDRV CCAAAAAGCA ITLYLKEKKYATTCCAAAAA TITCRASQWIGSQL GAAACTATTCC SPCAWEVVR GCAGAAACTA SWYQQKPGKAPKLTGTCTTGCACG AEIMRSFSLS TTCCTGTCTTG LIMWRSSLQSGVPS AAATGATCCAG TNLQESLRSKCACGAAATGA RFSGSGSGTDFTLT CAAATATTCAA ETVAAPSDIQ TCCAGCAAATAISSLQPEDFATYYC TTTGTTTTCTA MTQSPSSLSA TTCAATTTGTT AQGAALPRTFGQGCAAAGGACTC SVGDRVTITC TTCTACAAAGG TKVEIKR ATCAGCCGCTT RASQWIGSQLACTCATCAGCC AAAEQKLISEEDL GGGATGAAAC SWYQQKPGK GCTTGGGATGA N* (SEQ IDNO: 384) TCTGTTAGATA APKLLIMWR AACTCTGTTAG AATTCTACACT SSLQSGVPSRATAAATTCTAC GAACTATATCA FSGSGSGTDF ACTGAACTATA ACAACTGAAC TLTISSLQPEDTCAACAACTGA GATCTAGAGGC FATYYCAQG ACGATCTAGA TTGCGTTATTC AALPRTFGQGGCTTGCGTTA AGGGTGTAGG GTKVEIKR TTCAGGGTGTA AGTTACTGAAA (SEQ IDGGAGTTACTGA CTCCCCTAATG NO: 386) AACTCCCCTAA AAAGAAGATT TGAAAGAAGACAATTCTAGCC TTCAATTCTAG GTTAGAAAATA CCGTTAGAAA CTTTCAGCGTA ATACTTTCAGCTCACATTGTAT GTATCACATTG TTAAAGGAAA TATTTAAAGGA AGAAATACTCC AAAGAAATACCCATGTGCATG TCCCCATGTGC GGAGGTGGTTA ATGGGAGGTG GAGCAGAAAT GTTAGAGCAGTATGAGGTCCT AAATTATGAG TCTCTCTTTCT GTCCTTCTCTC ACGAATTTGCA TTTCTACGAATAGAATCTTTGA TTGCAAGAATC GATCTAAGGA TTTGAGATCTA AACCGTCGCTG AGGAAACCGTCTCCATCTGAC CGCTGCTCCAT ATCCAGATGAC CTGACATCCAG CCAGTCTCCAT ATGACCCAGTCCCTCCCTGTCT TCCATCCTCCC GCATCTGTAGG TGTCTGCATCT AGACCGTGTCA GTAGGAGACCCCATCACTTGC GTGTCACCATC CGGGCAAGTC ACTTGCCGGGC AGTGGATTGGG AAGTCAGTGGTCTCAGTTATC ATTGGGTCTCA TTGGTACCAGC GTTATCTTGGT AGAAACCAGG ACCAGCAGAAGAAAGCCCCTA ACCAGGGAAA AGCTCCTGATC GCCCCTAAGCT ATGTGGCGTTC CCTGATCATGTCTCGTTGCAAA GGCGTTCCTCG GTGGGGTCCCA TTGCAAAGTGG TCACGTTTCAG GGTCCCATCACTGGCAGTGGAT GTTTCAGTGGC CTGGGACAGAT AGTGGATCTGG TTCACTCTCAC GACAGATTTCACATCAGCAGTC CTCTCACCATC TGCAACCTGAA AGCAGTCTGCA GATTTTGCTAC ACCTGAAGATTGTACTACTGTG TTGCTACGTAC CTCAGGGTGCG TACTGTGCTCA GCGTTGCCTAG GGGTGCGGCGGACGTTCGGCC TTGCCTAGGAC AAGGGACCAA GTTCGGCCAAG GGTGGAAATC GGACCAAGGTAAACGGGCGG GGAAATCAAA CCGCAGAACA CGG (SEQ ID AAAACTCATC NO: 387)TCAGAAGAGG ATCTGAATTA A (SEQ ID NO: 385) DMS732 CDLPQTHSLGSRRTTGCGACTTGCC CDLPQTHSLG TGCGACTTGCC (IFNα2b- LMLLAQMRRISLFS ACAGACACATSRRTLMLLA ACAGACACAT DOM7h- CLKDRHDFGFPQE AGTTTGGGATC QMRRISLFSCAGTTTGGGATC 14-10) EFGNQFQKAETIPV AAGAAGAACA LKDRHDFGFP AAGAAGAACALHEMIQQIFNLFST TTGATGTTATT QEEFGNQFQ TTGATGTTATT KDSSAAWDETLLDAGCACAAATG KAETIPVLHE AGCACAAATG KFYTELYQQLNDL CGTAGAATTTC MIQQIFNLFSCGTAGAATTTC EACVIQGVGVTETP TTTGTTCTCTT TKDSSAAWD TTTGTTCTCTTLMKEDSILAVRKY GTCTAAAGGAC ETLLDKFYTE GTCTAAAGGA FQRITLYLKEKKYSCGTCACGACTT LYQQLNDLE CCGTCACGACT PCAWEVVRAEIMR CGGATTCCCTC ACVIQGVGVTCGGATTCCCT SFSLSTNLQESLRS AGGAAGAGTTT TETPLMKEDS CAGGAAGAGTKETVAAPSDIQMT GGAAACCAATT ILAVRKYFQR TTGGAAACCA QSPSSLSASVGDRVCCAAAAAGCA ITLYLKEKKY ATTCCAAAAA TITCRASQWIGSQL GAAACTATTCC SPCAWEVVRGCAGAAACTA SWYQQKPGKAPKL TGTCTTGCACG AEIMRSFSLS TTCCTGTCTTGLIMWRSSLQSGVPS AAATGATCCAG TNLQESLRSK CACGAAATGA RFSGSGSGTDFTLTCAAATATTCAA ETVAAPSDIQ TCCAGCAAATA ISSLQPEDFATYYC TTTGTTTTCTA MTQSPSSLSATTCAATTTGTT AQGLRHPKTFGQG CAAAGGACTC SVGDRVTITC TTCTACAAAGG TKVEIKRATCAGCCGCTT RASQWIGSQL ACTCATCAGCC AAAEQKLISEEDL GGGATGAAAC SWYQQKPGKGCTTGGGATGA N* (SEQ ID NO: 388) TCTGTTAGATA APKLLIMWR AACTCTGTTAGAATTCTACACT SSLQSGVPSR ATAAATTCTAC GAACTATATCA FSGSGSGTDF ACTGAACTATAACAACTGAAC TLTISSLQPED TCAACAACTGA GATCTAGAGGC FATYYCAQG ACGATCTAGATTGCGTTATTC LRHPKTFGQ GGCTTGCGTTA AGGGTGTAGG GTKVEIKR TTCAGGGTGTAAGTTACTGAAA (SEQ ID GGAGTTACTGA CTCCCCTAATG NO: 390) AACTCCCCTAAAAAGAAGATT TGAAAGAAGA CAATTCTAGCC TTCAATTCTAG GTTAGAAAATA CCGTTAGAAACTTTCAGCGTA ATACTTTCAGC TCACATTGTAT GTATCACATTG TTAAAGGAAA TATTTAAAGGAAGAAATACTCC AAAGAAATAC CCATGTGCATG TCCCCATGTGC GGAGGTGGTTA ATGGGAGGTGGAGCAGAAAT GTTAGAGCAG TATGAGGTCCT AAATTATGAG TCTCTCTTTCT GTCCTTCTCTCACGAATTTGCA TTTCTACGAAT AGAATCTTTGA TTGCAAGAATC GATCTAAGGA TTTGAGATCTAAACCGTCGCTG AGGAAACCGT CTCCATCTGAC CGCTGCTCCAT ATCCAGATGAC CTGACATCCAGCCAGTCTCCAT ATGACCCAGTC CCTCCCTGTCT TCCATCCTCCC GCATCTGTAGG TGTCTGCATCTAGACCGTGTCA GTAGGAGACC CCATCACTTGC GTGTCACCATC CGGGCAAGTC ACTTGCCGGGCAGTGGATTGGG AAGTCAGTGG TCTCAGTTATC ATTGGGTCTCA TTGGTACCAGC GTTATCTTGGTAGAAACCAGG ACCAGCAGAA GAAAGCCCCTA ACCAGGGAAA AGCTCCTGATC GCCCCTAAGCTATGTGGCGTTC CCTGATCATGT CTCGTTGCAAA GGCGTTCCTCG GTGGGGTCCCA TTGCAAAGTGGTCACGTTTCAG GGTCCCATCAC TGGCAGTGGAT GTTTCAGTGGC CTGGGACAGAT AGTGGATCTGGTTCACTCTCAC GACAGATTTCA CATCAGCAGTC CTCTCACCATC TGCAACCTGAA AGCAGTCTGCAGATTTTGCTAC ACCTGAAGATT GTACTACTGTG TTGCTACGTAC CTCAGGGTTTG TACTGTGCTCAAGGCATCCTAA GGGTTTGAGGC GACGTTCGGCC ATCCTAAGACG AAGGGACCAA TTCGGCCAAGGGGTGGAAATC GACCAAGGTG AAACGGGCGG GAAATCAAAC CCGCAGAACA GG (SEQ IDAAAACTCATC NO: 391) TCAGAAGAGG ATCTGAATTA A (SEQ ID NO: 389) DMS7323CDLPQTHSLGSRRT TGCGACTTGCC CDLPQTHSLG TGCGACTTGCC (IFNα2b-LMLLAQMRRISLFS ACAGACACAT SRRTLMLLA ACAGACACAT DOM7h- CLKDRHDFGFPQEAGTTTGGGATC QMRRISLFSC AGTTTGGGATC 14-18) EFGNQFQKAETIPV AAGAAGAACALKDRHDFGFP AAGAAGAACA LHEMIQQIFNLFST TTGATGTTATT QEEFGNQFQ TTGATGTTATTKDSSAAWDETLLD AGCACAAATG KAETIPVLHE AGCACAAATG KFYTELYQQLNDL CGTAGAATTTCMIQQIFNLFS CGTAGAATTTC EACVIQGVGVTETP TTTGTTCTCTT TKDSSAAWD TTTGTTCTCTTLMKEDSILAVRKY GTCTAAAGGAC ETLLDKFYTE GTCTAAAGGA FQRITLYLKEKKYSCGTCACGACTT LYQQLNDLE CCGTCACGACT PCAWEVVRAEIMR CGGATTCCCTC ACVIQGVGVTCGGATTCCCT SFSLSTNLQESLRS AGGAAGAGTTT TETPLMKEDS CAGGAAGAGTKETVAAPSDIQMT GGAAACCAATT ILAVRKYFQR TTGGAAACCA QSPSSLSASVGDRVCCAAAAAGCA ITLYLKEKKY ATTCCAAAAA TITCRASQWIGSQL GAAACTATTCC SPCAWEVVRGCAGAAACTA SWYQQKPGKAPKL TGTCTTGCACG AEIMRSFSLS TTCCTGTCTTGLIMWRSSLQSGVPS AAATGATCCAG TNLQESLRSK CACGAAATGA RFSGSGSGTDFTLTCAAATATTCAA ETVAAPSDIQ TCCAGCAAATA ISSLQPEDFATYYC TTTGTTTTCTA MTQSPSSLSATTCAATTTGTT AQGLMKPMTFGQ CAAAGGACTC SVGDRVTITC TTCTACAAAGG GTKVEIKRAAAEQATCAGCCGCTT RASQWIGSQL ACTCATCAGCC KLISEEDLN* (SEQ GGGATGAAAC SWYQQKPGKGCTTGGGATGA ID NO: 392) TCTGTTAGATA APKLLIMWR AACTCTGTTAG AATTCTACACTSSLQSGVPSR ATAAATTCTAC GAACTATATCA FSGSGSGTDF ACTGAACTATA ACAACTGAACTLTISSLQPED TCAACAACTGA GATCTAGAGGC FATYYCAQG ACGATCTAGA TTGCGTTATTCLMKPMTFGQ GGCTTGCGTTA AGGGTGTAGG GTKVEIKR TTCAGGGTGTA AGTTACTGAAA (SEQID GGAGTTACTGA CTCCCCTAATG NO: 394) AACTCCCCTAA AAAGAAGATT TGAAAGAAGACAATTCTAGCC TTCAATTCTAG GTTAGAAAATA CCGTTAGAAA CTTTCAGCGTA ATACTTTCAGCTCACATTGTAT GTATCACATTG TTAAAGGAAA TATTTAAAGGA AGAAATACTCC AAAGAAATACCCATGTGCATG TCCCCATGTGC GGAGGTGGTTA ATGGGAGGTG GAGCAGAAAT GTTAGAGCAGTATGAGGTCCT AAATTATGAG TCTCTCTTTCT GTCCTTCTCTC ACGAATTTGCA TTTCTACGAATAGAATCTTTGA TTGCAAGAATC GATCTAAGGA TTTGAGATCTA AACCGTCGCTG AGGAAACCGTCTCCATCTGAC CGCTGCTCCAT ATCCAGATGAC CTGACATCCAG CCAGTCTCCAT ATGACCCAGTCCCTCCCTGTCT TCCATCCTCCC GCATCTGTAGG TGTCTGCATCT AGACCGTGTCA GTAGGAGACCCCATCACTTGC GTGTCACCATC CGGGCAAGTC ACTTGCCGGGC AGTGGATTGGG AAGTCAGTGGTCTCAGTTATC ATTGGGTCTCA TTGGTACCAGC GTTATCTTGGT AGAAACCAGG ACCAGCAGAAGAAAGCCCCTA ACCAGGGAAA AGCTCCTGATC GCCCCTAAGCT ATGTGGCGTTC CCTGATCATGTCTCGTTGCAAA GGCGTTCCTCG GTGGGGTCCCA TTGCAAAGTGG TCACGTTTCAG GGTCCCATCACTGGCAGTGGAT GTTTCAGTGGC CTGGGACAGAT AGTGGATCTGG TTCACTCTCAC GACAGATTTCACATCAGCAGTC CTCTCACCATC TGCAACCTGAA AGCAGTCTGCA GATTTTGCTAC ACCTGAAGATTGTACTACTGTG TTGCTACGTAC CTCAGGGTCTT TACTGTGCTCA ATGAAGCCTAT GGGTCTTATGAGACGTTCGGCC AGCCTATGACG AAGGGACCAA TTCGGCCAAGG GGTGGAAATC GACCAAGGTGAAACGGGCGG GAAATCAAAC CCGCAGAACA GG (SEQ ID AAAACTCATC NO: 395)TCAGAAGAGG ATCTGAATTA A (SEQ ID NO: 393) DMS7324 CDLPQTHSLGSRRTTGCGACTTGCC CDLPQTHSLG TGCGACTTGCC (IFNα2b- LMLLAQMRRISLFS ACAGACACATSRRTLMLLA ACAGACACAT DOM7h- CLKDRHDFGFPQE AGTTTGGGATC QMRRISLFSCAGTTTGGGATC 14-19) EFGNQFQKAETIPV AAGAAGAACA LKDRHDFGFP AAGAAGAACALHEMIQQIFNLFST TTGATGTTATT QEEFGNQFQ TTGATGTTATT KDSSAAWDETLLDAGCACAAATG KAETIPVLHE AGCACAAATG KFYTELYQQLNDL CGTAGAATTTC MIQQIFNLFSCGTAGAATTTC EACVIQGVGVTETP TTTGTTCTCTT TKDSSAAWD TTTGTTCTCTTLMKEDSILAVRKY GTCTAAAGGAC ETLLDKFYTE GTCTAAAGGA FQRITLYLKEKKYSCGTCACGACTT LYQQLNDLE CCGTCACGACT PCAWEVVRAEIMR CGGATTCCCTC ACVIQGVGVTCGGATTCCCT SFSLSTNLQESLRS AGGAAGAGTTT TETPLMKEDS CAGGAAGAGTKETVAAPSDIQMT GGAAACCAATT ILAVRKYFQR TTGGAAACCA QSPSSLSASVGDRVCCAAAAAGCA ITLYLKEKKY ATTCCAAAAA TISCRASQWIGSQL GAAACTATTCC SPCAWEVVRGCAGAAACTA SWYQQKPGEAPKL TGTCTTGCACG AEIMRSFSLS TTCCTGTCTTGLIMWRSSLQSGVPS AAATGATCCAG TNLQESLRSK CACGAAATGA RFSGSGSGTDFTLTCAAATATTCAA ETVAAPSDIQ TCCAGCAAATA ISSLQPEDFATYYC TTTGTTTTCTA MTQSPSSLSATTCAATTTGTT AQGAALPRTFGQG CAAAGGACTC SVGDRVTISC TTCTACAAAGG TKVEIKRATCAGCCGCTT RASQWIGSQL ACTCATCAGCC AAAEQKLISEEDL GGGATGAAAC SWYQQKPGEGCTTGGGATGA N* (SEQ ID NO: 396) TCTGTTAGATA APKLLIMWR AACTCTGTTAGAATTCTACACT SSLQSGVPSR ATAAATTCTAC GAACTATATCA FSGSGSGTDF ACTGAACTATAACAACTGAAC TLTISSLQPED TCAACAACTGA GATCTAGAGGC FATYYCAQG ACGATCTAGATTGCGTTATTC AALPRTFGQ GGCTTGCGTTA AGGGTGTAGG GTKVEIKR TTCAGGGTGTAAGTTACTGAAA (SEQ ID GGAGTTACTGA CTCCCCTAATG NO: 398) AACTCCCCTAAAAAGAAGATT TGAAAGAAGA CAATTCTAGCC TTCAATTCTAG GTTAGAAAATA CCGTTAGAAACTTTCAGCGTA ATACTTTCAGC TCACATTGTAT GTATCACATTG TTAAAGGAAA TATTTAAAGGAAGAAATACTCC AAAGAAATAC CCATGTGCATG TCCCCATGTGC GGAGGTGGTTA ATGGGAGGTGGAGCAGAAAT GTTAGAGCAG TATGAGGTCCT AAATTATGAG TCTCTCTTTCT GTCCTTCTCTCACGAATTTGCA TTTCTACGAAT AGAATCTTTGA TTGCAAGAATC GATCTAAGGA TTTGAGATCTAAACCGTCGCTG AGGAAACCGT CTCCATCTGAC CGCTGCTCCAT ATCCAGATGAC CTGACATCCAGCCAGTcTCCAT ATGACCCAGTc CCTCCCTGTCT TCCATCCTCCC GCATCTGTAGG TGTCTGCATCTAGACCGTGTCA GTAGGAGACC CCATCTCTTGC GTGTCACCATC CGGGCAAGTC TCTTGCCGGGCAGTGGATTGGG AAGTCAGTGG TCTCAGTTATC ATTGGGTCTCA TTGGTACCAGC GTTATCTTGGTAGAAACCAGG ACCAGCAGAA GGAAGCCCCTA ACCAGGGGAA AGCTCCTGATC GCCCCTAAGCTATGTGGCGTTC CCTGATCATGT CTCGTTGCAAA GGCGTTCCTCG GTGGGGTCCCA TTGCAAAGTGGTCACGTTTCAG GGTCCCATCAC TGGCAGTGGAT GTTTCAGTGGC CTGGGACAGAT AGTGGATCTGGTTCACTCTCAC GACAGATTTCA CATCAGCAGTC CTCTCACCATC TGCAACCTGAA AGCAGTCTGCAGATTTTGCTAC ACCTGAAGATT GTACTACTGTG TTGCTACGTAC CTCAGGGTGCG TACTGTGCTCAGCGTTGCCTAG GGGTGCGGCG GACGTTCGGCC TTGCCTAGGAC AAGGGACCAA GTTCGGCCAAGGGTGGAAATC GGACCAAGGT AAACGGGCGG GGAAATCAAA CCGCAGAACA CGG (SEQ IDAAAACTCATC NO: 399) TCAGAAGAGG ATCTGAATTA A (SEQ ID NO: 397) DMS7325CDLPQTHSLGSRRT TGCGACTTGCC CDLPQTHSLG TGCGACTTGCC (IFNα2b-LMLLAQMRRISLFS ACAGACACAT SRRTLMLLA ACAGACACAT DOM7h- CLKDRHDFGFPQEAGTTTGGGATC QMRRISLFSC AGTTTGGGATC 11) EFGNQFQKAETIPV AAGAAGAACALKDRHDFGFP AAGAAGAACA LHEMIQQIFNLFST TTGATGTTATT QEEFGNQFQ TTGATGTTATTKDSSAAWDETLLD AGCACAAATG KAETIPVLHE AGCACAAATG KFYTELYQQLNDL CGTAGAATTTCMIQQIFNLFS CGTAGAATTTC EACVIQGVGVTETP TTTGTTCTCTT TKDSSAAWD TTTGTTCTCTTLMKEDSILAVRKY GTCTAAAGGAC ETLLDKFYTE GTCTAAAGGA FQRITLYLKEKKYSCGTCACGACTT LYQQLNDLE CCGTCACGACT PCAWEVVRAEIMR CGGATTCCCTC ACVIQGVGVTCGGATTCCCT SFSLSTNLQESLRS AGGAAGAGTTT TETPLMKEDS CAGGAAGAGTKETVAAPSDIQMT GGAAACCAATT ILAVRKYFQR TTGGAAACCA QSPSSLSASVGDRVCCAAAAAGCA ITLYLKEKKY ATTCCAAAAA TITCRASRPIGTTLS GAAACTATTCC SPCAWEVVRGCAGAAACTA WYQQKPGKAPKLL TGTCTTGCACG AEIMRSFSLS TTCCTGTCTTGIWFGSRLQSGVPSR AAATGATCCAG TNLQESLRSK CACGAAATGA FSGSGSGTDFTLTISCAAATATTCAA ETVAAPSDIQ TCCAGCAAATA SLQPEDFATYYCA TTTGTTTTCTA MTQSPSSLSATTCAATTTGTT QAGTHPTTFGQGT CAAAGGACTC SVGDRVTITC TTCTACAAAGG KVEIKRATCAGCCGCTT RASRPIGTTL ACTCATCAGCC AAAEQKLISEEDL GGGATGAAAC SWYQQKPGKGCTTGGGATGA N* (SEQ ID NO: 400) TCTGTTAGATA APKLLIWFGS AACTCTGTTAGAATTCTACACT RLQSGVPSRF ATAAATTCTAC GAACTATATCA SGSGSGTDFT ACTGAACTATAACAACTGAAC LTISSLQPEDF TCAACAACTGA GATCTAGAGGC ATYYCAQAG ACGATCTAGATTGCGTTATTC THPTTFGQGT GGCTTGCGTTA AGGGTGTAGG KVEIKR (SEQ TTCAGGGTGTAAGTTACTGAAA ID NO: 402) GGAGTTACTGA CTCCCCTAATG AACTCCCCTAA AAAGAAGATTTGAAAGAAGA CAATTCTAGCC TTCAATTCTAG GTTAGAAAATA CCGTTAGAAA CTTTCAGCGTAATACTTTCAGC TCACATTGTAT GTATCACATTG TTAAAGGAAA TATTTAAAGGA AGAAATACTCCAAAGAAATAC CCATGTGCATG TCCCCATGTGC GGAGGTGGTTA ATGGGAGGTG GAGCAGAAATGTTAGAGCAG TATGAGGTCCT AAATTATGAG TCTCTCTTTCT GTCCTTCTCTC ACGAATTTGCATTTCTACGAAT AGAATCTTTGA TTGCAAGAATC GATCTAAGGA TTTGAGATCTA AACCGTCGCTGAGGAAACCGT CTCCATCTGAC CGCTGCTCCAT ATCCAGATGAC CTGACATCCAG CCAGTCTCCATATGACCCAGTC CCTCCCTGTCT TCCATCCTCCC GCATCTGTAGG TGTCTGCATCT AGACCGTGTCAGTAGGAGACC CCATCACTTGC GTGTCACCATC CGGGCAAGTC ACTTGCCGGGC GTCCGATTGGGAAGTCGTCCGA ACGACGTTAAG TTGGGACGAC TTGGTACCAGC GTTAAGTTGGT AGAAACCAGGACCAGCAGAA GAAAGCCCCTA ACCAGGGAAA AGCTCCTGATC GCCCCTAAGCT TGGTTTGGTTCCCTGATCTGGT CCGGTTGCAAA TTGGTTCCCGG GTGGGGTCCCA TTGCAAAGTGG TCACGTTTCAGGGTCCCATCAC TGGCAGTGGAT GTTTCAGTGGC CTGGGACAGAT AGTGGATCTGG TTCACTCTCACGACAGATTTCA CATCAGCAGTC CTCTCACCATC TGCAACCTGAA AGCAGTCTGCA GATTTTGCTACACCTGAAGATT GTACTACTGTG TTGCTACGTAC CGCAGGCTGG TACTGTGCGCA GACGCATCCTAGGCTGGGACG CGACGTTCGGC CATCCTACGAC CAAGGGACCA GTTCGGCCAAG AGGTGGAAATGGACCAAGGT CAAACGGGCG GGAAATCAAA GCCGCAGAAC CGG (SEQ ID AAAAACTCAT NO:403) CTCAGAAGAG GATCTGAATT AA (SEQ ID NO: 401) DMS7326 CDLPQTHSLGSRRTTGCGACTTGCC CDLPQTHSLG TGCGACTTGCC (IFNα2b- LMLLAQMRRISLFS ACAGACACATSRRTLMLLA ACAGACACAT DOM7h- CLKDRHDFGFPQE AGTTTGGGATC QMRRISLFSCAGTTTGGGATC 11-12) EFGNQFQKAETIPV AAGAAGAACA LKDRHDFGFP AAGAAGAACALHEMIQQIFNLFST TTGATGTTATT QEEFGNQFQ TTGATGTTATT KDSSAAWDETLLDAGCACAAATG KAETIPVLHE AGCACAAATG KFYTELYQQLNDL CGTAGAATTTC MIQQIFNLFSCGTAGAATTTC EACVIQGVGVTETP TTTGTTCTCTT TKDSSAAWD TTTGTTCTCTTLMKEDSILAVRKY GTCTAAAGGAC ETLLDKFYTE GTCTAAAGGA FQRITLYLKEKKYSCGTCACGACTT LYQQLNDLE CCGTCACGACT PCAWEVVRAEIMR CGGATTCCCTC ACVIQGVGVTCGGATTCCCT SFSLSTNLQESLRS AGGAAGAGTTT TETPLMKEDS CAGGAAGAGTKETVAAPSDIQMT GGAAACCAATT ILAVRKYFQR TTGGAAACCA QSPSSLSASVGDRVCCAAAAAGCA ITLYLKEKKY ATTCCAAAAA TITCRASRPIGTML GAAACTATTCC SPCAWEVVRGCAGAAACTA SWYQQKPGKAPKL TGTCTTGCACG AEIMRSFSLS TTCCTGTCTTGLILFGSRLQSGVPS AAATGATCCAG TNLQESLRSK CACGAAATGA RFSGSGSGTDFTLTCAAATATTCAA ETVAAPSDIQ TCCAGCAAATA ISSLQPEDFATYYC TTTGTTTTCTA MTQSPSSLSATTCAATTTGTT AQAGTHPTTFGQG CAAAGGACTC SVGDRVTITC TTCTACAAAGG TKVEIKRATCAGCCGCTT RASRPIGTML ACTCATCAGCC AAAEQKLISEEDL GGGATGAAAC SWYQQKPGKGCTTGGGATGA N* (SEQ ID NO: 404) TCTGTTAGATA APKLLILFGS AACTCTGTTAGAATTCTACACT RLQSGVPSRF ATAAATTCTAC GAACTATATCA SGSGSGTDFT ACTGAACTATAACAACTGAAC LTISSLQPEDF TCAACAACTGA GATCTAGAGGC ATYYCAQAG ACGATCTAGATTGCGTTATTC THPTTFGQGT GGCTTGCGTTA AGGGTGTAGG KVEIKR (SEQ TTCAGGGTGTAAGTTACTGAAA ID NO: 406) GGAGTTACTGA CTCCCCTAATG AACTCCCCTAA AAAGAAGATTTGAAAGAAGA CAATTCTAGCC TTCAATTCTAG GTTAGAAAATA CCGTTAGAAA CTTTCAGCGTAATACTTTCAGC TCACATTGTAT GTATCACATTG TTAAAGGAAA TATTTAAAGGA AGAAATACTCCAAAGAAATAC CCATGTGCATG TCCCCATGTGC GGAGGTGGTTA ATGGGAGGTG GAGCAGAAATGTTAGAGCAG TATGAGGTCCT AAATTATGAG TCTCTCTTTCT GTCCTTCTCTC ACGAATTTGCATTTCTACGAAT AGAATCTTTGA TTGCAAGAATC GATCTAAGGA TTTGAGATCTA AACCGTCGCTGAGGAAACCGT CTCCATCTGAC CGCTGCTCCAT ATCCAGATGAC CTGACATCCAG CCAGTCTCCATATGACCCAGTC CCTCCCTGTCT TCCATCCTCCC GCATCTGTAGG TGTCTGCATCT AGACCGTGTCAGTAGGAGACC CCATCACTTGC GTGTCACCATC CGGGCAAGTC ACTTGCCGGGC GTCCGATTGGGAAGTCGTCCGA ACGATGTTAAG TTGGGACGATG TTGGTACCAGC TTAAGTTGGTA AGAAACCAGGCCAGCAGAAA GAAAGCCCCTA CCAGGGAAAG AGCTCCTGATC CCCCTAAGCTC TTGTTTGGTTCCTGATCTTGTT CCGGTTGCAAA TGGTTCCCGGT GTGGGGTCCCA TGCAAAGTGG TCACGTTTCAGGGTCCCATCAC TGGCAGTGGAT GTTTCAGTGGC CTGGGACAGAT AGTGGATCTGG TTCACTCTCACGACAGATTTCA CATCAGCAGTC CTCTCACCATC TGCAACCTGAA AGCAGTCTGCA GATTTTGCTACACCTGAAGATT GTACTACTGTG TTGCTACGTAC CGCAGGCTGG TACTGTGCGCA GACGCATCCTAGGCTGGGACG CGACGTTCGGC CATCCTACGAC CAAGGGACCA GTTCGGCCAAG AGGTGGAAATGGACCAAGGT CAAACGGGCG GGAAATCAAA GCCGCAGAAC CGG (SEQ ID AAAAACTCAT NO:407) CTCAGAAGAG GATCTGAATT AA (SEQ ID NO: 405 DMS7327 CDLPQTHSLGSRRTTGCGACTTGCC CDLPQTHSLG TGCGACTTGCC (IFNα2b- LMLLAQMRRISLFS ACAGACACATSRRTLMLLA ACAGACACAT DOM7h- CLKDRHDFGFPQE AGTTTGGGATC QMRRISLFSCAGTTTGGGATC 11-15) EFGNQFQKAETIPV AAGAAGAACA LKDRHDFGFP AAGAAGAACALHEMIQQIFNLFST TTGATGTTATT QEEFGNQFQ TTGATGTTATT KDSSAAWDETLLDAGCACAAATG KAETIPVLHE AGCACAAATG KFYTELYQQLNDL CGTAGAATTTC MIQQIFNLFSCGTAGAATTTC EACVIQGVGVTETP TTTGTTCTCTT TKDSSAAWD TTTGTTCTCTTLMKEDSILAVRKY GTCTAAAGGAC ETLLDKFYTE GTCTAAAGGA FQRITLYLKEKKYSCGTCACGACTT LYQQLNDLE CCGTCACGACT PCAWEVVRAEIMR CGGATTCCCTC ACVIQGVGVTCGGATTCCCT SFSLSTNLQESLRS AGGAAGAGTTT TETPLMKEDS CAGGAAGAGTKETVAAPSDIQMT GGAAACCAATT ILAVRKYFQR TTGGAAACCA QSPSSLSASVGDRVCCAAAAAGCA ITLYLKEKKY ATTCCAAAAA TITCRASRPIGTML GAAACTATTCC SPCAWEVVRGCAGAAACTA SWYQQKPGKAPKL TGTCTTGCACG AEIMRSFSLS TTCCTGTCTTGLILAFSRLQSGVPS AAATGATCCAG TNLQESLRSK CACGAAATGA RFSGSGSGTDFTLTCAAATATTCAA ETVAAPSDIQ TCCAGCAAATA ISSLQPEDFATYYC TTTGTTTTCTA MTQSPSSLSATTCAATTTGTT AQAGTHPTTFGQG CAAAGGACTC SVGDRVTITC TTCTACAAAGG TKVEIKRATCAGCCGCTT RASRPIGTML ACTCATCAGCC AAAEQKLISEEDL GGGATGAAAC SWYQQKPGKGCTTGGGATGA N* (SEQ ID NO: 408) TCTGTTAGATA APKLLILAFS AACTCTGTTAGAATTCTACACT RLQSGVPSRF ATAAATTCTAC GAACTATATCA SGSGSGTDFT ACTGAACTATAACAACTGAAC LTISSLQPEDF TCAACAACTGA GATCTAGAGGC ATYYCAQAG ACGATCTAGATTGCGTTATTC THPTTFGQGT GGCTTGCGTTA AGGGTGTAGG KVEIKR (SEQ TTCAGGGTGTAAGTTACTGAAA ID NO: 410) GGAGTTACTGA CTCCCCTAATG AACTCCCCTAA AAAGAAGATTTGAAAGAAGA CAATTCTAGCC TTCAATTCTAG GTTAGAAAATA CCGTTAGAAA CTTTCAGCGTAATACTTTCAGC TCACATTGTAT GTATCACATTG TTAAAGGAAA TATTTAAAGGA AGAAATACTCCAAAGAAATAC CCATGTGCATG TCCCCATGTGC GGAGGTGGTTA ATGGGAGGTG GAGCAGAAATGTTAGAGCAG TATGAGGTCCT AAATTATGAG TCTCTCTTTCT GTCCTTCTCTC ACGAATTTGCATTTCTACGAAT AGAATCTTTGA TTGCAAGAATC GATCTAAGGA TTTGAGATCTA AACCGTCGCTGAGGAAACCGT CTCCATCTGAC CGCTGCTCCAT ATCCAGATGAC CTGACATCCAG CCAGTCTCCATATGACCCAGTC CCTCCCTGTCT TCCATCCTCCC GCATCTGTAGG TGTCTGCATCT AGACCGTGTCAGTAGGAGACC CCATCACTTGC GTGTCACCATC CGGGCAAGTC ACTTGCCGGGC GTCCGATTGGGAAGTCGTCCGA ACGATGTTAAG TTGGGACGATG TTGGTACCAGC TTAAGTTGGTA AGAAACCAGGCCAGCAGAAA GAAAGCCCCTA CCAGGGAAAG AGCTCCTGATC CCCCTAAGCTC CTTGCTTTTTCCTGATCCTTGC CCGTTTGCAAA TTTTTCCCGTT GTGGGGTCCCA TGCAAAGTGG TCACGTTTCAGGGTCCCATCAC TGGCAGTGGAT GTTTCAGTGGC CTGGGACAGAT AGTGGATCTGG TTCACTCTCACGACAGATTTCA CATCAGCAGTC CTCTCACCATC TGCAACCTGAA AGCAGTCTGCA GATTTTGCTACACCTGAAGATT GTACTACTGCG TTGCTACGTAC CGCAGGCTGG TACTGCGCGCA GACGCATCCTAGGCTGGGACG CGACGTTCGGC CATCCTACGAC CAAGGGACCA GTTCGGCCAAG AGGTGGAAATGGACCAAGGT CAAACGGGCG GGAAATCAAA GCCGCAGAAC CGG (SEQ ID AAAAACTCAT NO:411) CTCAGAAGAG GATCTGAATT AA (SEQ ID NO: 409) The amino acid andnucleotide sequences highlighted in bold represents the cloning site andMYC tag. *represents the stop codon at the end of the gene.

Affinity Determination and Biophysical Characterisation:

To determine the binding affinity (K_(D)) of the AlbudAb-IFNα2b fusionproteins to each serum albumin; purified fusion proteins were analysedby BIAcore over albumin (immobilised by primary-amine coupling onto CM5chips; BIAcore) using fusion protein concentrations from 5000 nM to 39nM (5000 nM, 2500 nM, 1250 nM, 625 nM, 312 nM, 156 nM, 78 nM, 39 nM) inHBS-EP BIAcore buffer.

TABLE 12 Affinity to SA Affinity to AlbudAb Fusion SA (nM) Kd Ka RatDOM7h-14 IFNα2b  350 4.500E−02 1.28E+05 DOM7h-14-10 IFNα2b  16 4.970E−035.90E+05 DOM7h-14-18 IFNα2b  780 2.127E−01 5.80E+05 DOM7h-14-19 IFNα2b1900 1.206E−01 7.96E+04 DOM7h-11 IFNα2b 6000 7.500E−01 nd DOM7h-11-12IFNα2b 1700 3.100E−01 1.30E+05 DOM7h-11-15 IFNα2b  200 1.660E−021.50E+05 Cyno DOM7h-14 IFNα2b  60 1.32E−02 5.0E+05 DOM7h-14-10 IFNα2b 19 7.05E−03 4.50E+05 DOM7h-14-18 IFNα2b no binding no binding nobinding DOM7h-14-19 IFNα2b  520 8.47E−02 2.73E+05 DOM7h-11 IFNα2b 33003.59E−01 1.20E+05 DOM7h-11-12 IFNα2b  630 3.45E−01 7.00E+05 DOM7h-11-15IFNα2b  15 4.86E−03 3.60E+05 Mouse DOM7h-14 IFNα2b  240 3.21E−021.50E+06 DOM7h-14-10 IFNα2b  60 3.45E−02 6.86E+05 DOM7h-14-18 IFNα2b 180 1.50E−01 9.84E+05 DOM7h-14-19 IFNα2b  490 4.03E−02 1.19E+05DOM7h-11 IFNα2b 6000 1.55E−01 nd DOM7h-11-12 IFNα2b  150 9.49E−026.30E+05 DOM7h-11-15 IFNα2b  28 6.69E−03 2.80E+05 Human DOM7h-14 IFNα2b 244 2.21E−02 9.89E+04 DOM7h-14-10 IFNα2b  32 6.58E−03 3.48E+05DOM7h-14-18 IFNα2b  470 2.75E−01 6.15E+05 DOM7h-14-19 IFNα2b  3504.19E−02 1.55E+05 DOM7h-11 IFNα2b  670 2.02E−01 7.00E+05 DOM7h-11-12IFNα2b  500 1.66E−01 3.90E+05 DOM7h-11-15 IFNα2b  10 1.87E−03 3.50E+05

When IFNα2b is linked to the AlbudAb variants, in all cases the affinityof AlbudAb binding to serum albumin is reduced. DOM7h-14-10 andDOM7-11-15 retain improved binding affinity to serum albumin acrossspecies compared to parent. DOM7h-11-12 also shows improved bindingaffinity to serum albumin across species compared to parent.

TABLE 13 Biophysical Characterisation Biophysical parameters DMS SEC DSCAlbudAb Fusion number MALLS Tm(° C.) DOM7h-14 IFNα2b DMS7321 M/D 58-65DOM7h-14-10 IFNα2b DMS7322 M/D 55-65 DOM7h-14-18 IFNα2b DMS7323 M/D55-65 DOM7h-14-19 IFNα2b DMS7324 M/D 59-66 DOM7h-11 IFNα2b DMS7325 M/D65.8-66.2 DOM7h-11-12 IFNα2b DMS7326 M/D   67-67.3 DOM7h-11-15 IFNα2bDMS7327 M/D 56.3-66.2 Biophysical Characterisation was carried out bySEC MALLS and DSC as described above for the single AlbudAbs.

M/D indicates a monomer/dimer equilibrium as detected by SEC MALLS

We observed expression for all clones in Tabale 13 in the range of 17.5to 54 mg/L in HEK293.

For IFNα2b-DOM7h-14 and IFNα2b-DOM7h-11 variants, favorable biophysicalparameters and expression levels were maintained during affinitymaturation.

PK Determination for AlbudAb-IFNα2bfusions

AlbudAbs IFNα2b fusions DMS7321 (IFNα2b-DOM7h-14) DMS7322(IFNα2b-DOM7h-14-10) DMS7323 (IFNα2b-DOM7h-14-18), DMS7324(IFNα2b-DOM7h-14-19), DMS7325 (IFNα2b-DOM7h-11), DMS7326(IFNα2b-DOM7h-11-12), DMS7327 (IFNα2b-DOM7h-11-15) were expressed withthe myc tag at 20-50 mg quantities in HEK293 cells and purified fromculture supernatant using protein L affinity resin and eluted with 100mM glycine pH2. The proteins were concentrated to greater than 1 mg/ml,buffer exchanged into Dulbecco's PBS and endotoxin depleted using Q spincolumns (Vivascience).

For Rat PK, IFN-AlbudAbs were dosed as single i.v injections at 2.0mg/kg using 3 rats per compound. Serum samples were taken at 0.16, 1, 4,8, 24, 48, 72, 120, 168 hrs. Analysis of serum levels was by EASY ELISAaccording to manufacturers instructions (GE Healthcare, catalogue numberRPN5960).

For Mouse PK, DMS7322 (IFN2b-DOM7h-14-10) DMS7325 (IFN2b-DOM7h-11),DMS7326 (IFN2b-DOM7h-11-12), DMS7327 (IFN2b-DOM7h-11-15) all with myctags were dosed as single i.v injections at 2.0 mg/kg per dose group of3 subjects and serum samples taken at 10 mins; 1 h; 8h; 24h; 48h; 72h;96h. Analysis of serum levels was by EASY ELISA according tomanufacturers instructions (GE Healthcare, catalogue number RPN5960).

TABLE 14 PK parameters Albumin AUC CL t½ Vz Species AlbudAb Fusion K_(D)(nM) h × ug/ml ml/h/kg h ml/kg Rat 7h-14 IFNα2b 350 832.1 2.4 27 94.57h-14-10 IFNα2b 16 1380.7 1.5 35.8 75.2 7h-14-18 IFNα2b 780 691.2 2.922.4 93.7 7h-14-19 IFNα2b 1900 969.4 2.2 25 78.7 7h-11 IFNα2b 6000 327.96.5 11 101.9 7h-11-12 IFNα2b 1700 747.1 2.8 25.8 104.7 7h-11-15 IFNα2b200 1118.7 1.8 39.5 103.6 mouse 7h-14 IFNα2b 240 761.2 2.6 30.4 115.37h-14-10 IFNα2b 60 750.5 2.7 30.9 118.6 7h-11 IFNα2b 6000 493.9 4.0 8.851.2 7h-11-12 IFNα2b 150 439.6 4.5 21.5 140.9 7h-11-15 IFNα2b 28 971.82.1 33.6 99.6

Pharmacokinetic parameters derived from rat and mouse studies werefitted using a non-compartmental model. Key: AUC: Area under the curvefrom dosing time extrapolated to infinity; CL: clearance; t½: is thetime during which the blood concentration is halved; Vz: volume ofdistribution based on the terminal phase.

IFNα2b—AlbudAbs were tested in rat and mouse. For all IFNα2b-DOM7h-11variant fusion proteins in both rat and mouse, t½ is improved comparedto parent. The improvement in t½ correlates with the improved in vitroK_(D) to serum albumin. For IFNα2b-DOM7h-14-10 variants, the improvementin in vitro K_(D) to serum albumin also correlated to an improvement int½ in rat.

All IFNα2b-AlbudAb fusion proteins exhibit a 5 to 10-fold decrease inthe binding to RSA compared to the single AlbudAb. This effect is morepronounced (i.e. 10-fold) for the DOM7h-14 series than the DOM7h-11series (only 5-fold decrease).

Example 8 Further AlbudAb Fusions with Proteins, Peptides and NCEs

Various AlbudAbs fused to other chemical entities namely domainantibodies (dAbs), peptides and NCEs were tested. The results are shownin table 15.

TABLE 15 PK parameters Albumin AUC CL t½ Vz Species AlbudAb Fusion K_(D)(nM) h × ug/ml ml/h/kg h ml/kg Rat DOM7h-14 Exendin-4 2400 18 57.1 11901.9 DOM7h-14-10 Exendin-4 19 43.6 23.1 22.1 740.3 DOM7h-14-18Exendin-4 16000 16.9 75.7 9.4 1002.5 DOM7h-14-19 Exendin-4 17000 31.432.5 11.9 556.7 DOM7h-11 Exendin-4 24000 6.1 168 7.1 1684.1 DOM7h-11-12Exendin-4 1400 24.2 59.9 13 1068.7 DOM7h-11-15 Exendin-4 130 36.3 27.619.3 765.7 DOM7h14-10 NCE-GGGGSC 62 DOM7h14-10 NCE-TVAAPSC 35 HumanDOM7h-14 NCE 204 mouse DOM7h-11 DOM1m-21-23 234 10.7 4.7 72.5DOM7h-11-12 DOM1m-21-23 755 3.3 18 86.2 DOM7h-11-15 DOM1m-21-23 1008 2.517.4 62.4 Key: DOM1m-21-23 is an anti-TNFR1 dAb, Exendin-4 is a peptide(a GLP-1 agonist) of 39 amino acids length. NCE, NCE-GGGGSC andNCE-TVAAPSC are described below.

Previously we have described the use of genetic fusions with analbumin-binding dAb (AlbudAb) to extend the PK half-life of anti-TNFR1dAbs in vivo (see, eg, WO04003019, WO2006038027, WO2008149148).Reference is made to the protocols in these PCT applications. In thetable above, DOM1m-21-23 is an anti-mouse TNFR1 dAb.

To produce genetic fusions of exendin-4 or with DOM7h-14 (or otherAlbudAb) which binds serum albumin, the exendin-4-linker-AlbudAbsequence was cloned into the pTT-5 vector (obtainable from CNRC,Canada). In each case the exendin-4 was at the 5′ end of the constructand the dAb at the 3′ end. The linker was a (G₄S)₃ linker.Endotoxin-free DNA was prepared in E. coli using alkaline lysis (usingthe endotoxin-free plasmid Giga kit, obtainable from Qiagen CA) and usedto transfect HEK293E cells (obtainable from CNRC, Canada). Transfectionwas into 250 ml/flask of HEK293E cells at 1.75×10⁶ cells/ml using 333 ulof 293fectin (Invotrogen) and 250 ug of DNA per flask and expression wasat 30° C. for 5 days. The supernatant was harvested by centrifugationand purification was by affinity purification on protein L. Protein wasbatch bound to the resin, packed on a column and washed with 10 columnvolumes of PBS. Protein was eluted with 50 ml of 0.1 M glycine pH2 andneatralised with Tris pH8. Protein of the expected size was identifiedon an SDS-PAGE gel.

NCE Albudab Fusions:

A new chemical entity (NCE) AlbudAb fusion was tested. The NCE, a smallmolecule ADAMTS-4 inhibitor was synthesised with a PEG linker (PEG 4linker (ie 4 PEG molecules before the maleimide) and a maleimide groupfor conjugation to the AlbudAb. Conjugation of the NCE to the AlbudAb isvia an engineered cystine residue at amino acid position R108C, orfollowing a 5 amino acid (GGGGSC) or 6 amino acid (TVAAPSC) spacerengineered at the end of the AlbudAb. Briefly, the AlbudAb was reducedwith TCEP (Pierce, Catalogue Number 77720), desalted using a PD10 column(GE healthcare) into 25 mM Bis-Tris, 5 mM EDTA, 10% (v/v) glycerolpH6.5. A 5 fold molar excess of maleimide activated NCE was added inDMSO not to exceed 10% (V/V) final concentration. The reaction wasincubated over night at room temperature and dialysed extensively into20 mM Tris pH7.4

PEG Linker:

Sequences:

DOM7h-14 R108C: (SEQ ID NO: 412)DIQMTQSPSSLSASVGDRVTITCRASQWIGSQLSWYQQKPGKAPKLLIMWRSSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCAQGLRHPKTFG QGTKVEIKC

Nucleotide:

(SEQ ID NO: 413) GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACCGTGTCACCATCACTTGCCGGGCAAGTCAGTGGATTGGGTCTCAGTTATCTTGGTACCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCATGTGGCGTTCCTCGTTGCAAAGTGGGGTCCCATCACGTTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAACCTGAAGATTTTGCTACGTACTACTGTGCTCAGGGTTTGAGGCATCCTAAGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAATGC

See table 5 for the sequences of DOM7h-14-10/TVAAPSC andDOM7h-14-10/GGGGSC (ie, DOM7h-14-10/G4SC).

NCE-AlbudAbs DOM7h-14-10 GGGGSC and DOM7h14-10 TVAAPSC, exhibit a 5 to10 fold decrease in in vitro affinity (K_(D)) to RSA as determined byBIAcore when fused to the chemical entity. PK data are not available forthese molecules yet.

dAb-Albudab fusion: the 2 DOM7h-11 AlbudAbs with the highest affinity toRSA experience a 2-fold decrease in affinity to RSA as on BIAcore whenfused to a therapeutic domain antibody (DOM1m-21-23) compared to theunfused AlbudAb. The DOM7h-11 clone shows a micromolar K_(D) when fused(2.8 uM) as well as when unfused (˜5 uM).

Exendin 4-AlbudAb fusion: the effect of fusing the AlbudAbs to a peptideon the binding ability to RSA is about 10-fold, apart from DOM7h-14-10,which only shows a 4-fold decrease in binding. The effect, however, ismore pronounced for the DOM7h-14 series (except DOM7h-14-10) than itappears to be for the DOM7h-11 series.

For all the above data, the T½ of the fusion increased with improvedaffinity to the species' SA.

We generally classify Albudab-therapeutics as being therapeuticallyamenable (for treatment and/or prophylaxis of diseases, conditions orindications) when the AlbudAb-drug fusions show an affinity range(K_(D)) of from 0.1 nM to 10 mM for serum albumin binding.

We define the therapeutic ranges of AlbudAbs and AlbudAb fusions(Protein-AlbudAbs for example IFNα2b-DOM7h-14-10; Peptide-AlbudAbs forexample Exendin-4-DOM7h-14-10; dAb-AlbudAbs for exampleDOM1m21-23-DOM7h11-15; NCE-AlbudAb for example ADAMTS-4-DOM7h-14-10) asfollows: Affinity (K_(D)) ranges that are useful for therapy of chronicor acute conditions, diseases or indictions are shown. Also shown areaffinity ranges marked as “intermediate”. AlbudAbs and fusions in thisrange have utility for chronic or acute diseases, conditions orindications. In this way, the affinity of the AlbudAb or fusion forserum albumin can be tailored or chosen according to the disease,condition or indication to be addressed. As described above, theinvention provides AlbudAbs with affinities that allow for each AlbudAbto be categorised as “high affinity”, “medium affinity” or “lowaffinity”, thus enabling the skilled person to select the appropriateAlbudAb of the invention according to the therapy at hand. See FIG. 2.

Example 9 DOM7h-11-15^(S12P) Sequences

Amino Acid Sequence of DOM7h-11-15^(S12P) (SEQ ID NO: 414)DIQMTQSPSSLPASVGDRVTITCRASRPIGTMLSWYQQKPGKAPKLLILAFSRLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCAQAGTHPTTFGQ GTKVEIKR

An aspect of the invention provides a nucleic acid comprising thenucleotide sequence of DOM7h-11-15^(S12P) or a nucleotide sequence thatis at least 80% identical to said selected sequence. DOM7h-11-15^(S12P)was produced using the following nucleic acid sequence (the underlined Cdenotes the change (versus the nucleic acid encoding DOM7h-11-15)leading to a proline at position 12):—

(SEQ ID NO: 415) GACATCCAGATGACCCAGTCTCCATCCTCCCTGCCTGCATCTGTAGGAGACCGTGTCACCATCACTTGCCGGGCAAGTCGTCCGATTGGGACGATGTTAAGTTGGTACCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCCTTGCTTTTTCCCGTTTGCAAAGTGGGGTCCCATCACGTTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAACCTGAAGATTTTGCTACGTACTACTGCGCGCAGGCTGGGACGCATCCTACGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAACGG

DOM7h-11-15^(S12P) was constructed by using DOM7h-11-15 as a template ina PCR where a primer was used to introduce the S12P mutation. The primersequence is:—

(SEQ ID NO: 416) GCAACAGCGTCGACGGACATCCAGATGACCCAGTCTCCATCCTCCCTGCCTGCATCTGTAGG.

An alternative aspect of the invention provides a nucleic acidcomprising the nucleotide sequence of SEQ ID NO: 415 or a nucleotidesequence that is at least 80% identical to said selected sequence. Inone embodiment, DOM7h-11-15^(S12P) is encoded by, and expressed from, avector that contains a linker region and a C-terminal sequence encodinga protein or peptide drug or a single variable domain or other antibodyfragment to make the in-line protein fusion product. The linker, in oneembodiment, comprises the amino acid sequence TVA, eg, TVAAPS. Otheraspects of the invention are a vector comprising the nucleic acid; andan isolated host cell comprising the vector. The invention also providesa method of treating or preventing a disease or disorder in a patient,comprising administering at least one dose of DOM7h-11-15^(S12P) to saidpatient.

1. An anti-serum albumin (SA) immunoglobulin single variable domain variant of DOM7h-11 (DOM7h-11 as shown in FIG. 1), wherein the variant comprises at least one mutation in the FW2/CDR2 junction (positions 49 to 51, numbering according to Kabat) compared to DOM7h-11, and wherein the variant has from 2 to 8 changes compared to the amino acid sequence of DOM7h-11.
 2. The variant of claim 1, wherein position 49 (according to Kabat) is Leu.
 3. The variant of claim 1, wherein position 50 (according to Kabat) is Ala or Trp.
 4. The variant of claim 1, wherein position 51 (according to Kabat) is Phe or Asn.
 5. The variant of claim 1, wherein the variant comprises an amino acid sequence that is identical to the amino acid sequence of a single variable domain selected from DOM7h-11-3 (SEQ ID NO: 5), DOM7h-11-15 (SEQ ID NO: 2), DOM7h-11-12 (SEQ ID NO: 1) and DOM7h-11-19 (SEQ ID NO: 4) or has up to 4 changes compared to the selected amino acid sequence, provided that the amino acid sequence of the variant has at least one mutation in the FW2/CDR2 junction.
 6. The variant of claim 1, wherein the variant comprises an amino acid sequence that is identical to the amino acid sequence of DOM7h-11-15^(S12P)(SEQ ID NO: 414) or has up to 4 changes compared to the amino acid sequence of DOM7h-11-15^(S12P), provided that the amino acid sequence of the variant has at least one mutation in the FW2/CDR2 junction.
 7. An anti-serum albumin (SA) immunoglobulin single variable domain variant of DOM7h-11, wherein the variant comprises a Met at position 32 (numbering according to Kabat) compared to DOM7h-11 (as shown in FIG. 1), and wherein the variant has from 0 to 4 further changes compared to the amino acid sequence of DOM7h-11.
 8. The variant of claim 7, wherein the variant comprises at least one mutation in the FW2/CDR2 junction (positions 49 to 51, numbering according to Kabat) compared to DOM7h-11 (as shown in FIG. 1).
 9. The variant of claim 7, wherein the variant comprises at least one mutation compared to DOM7h-11 (as shown in FIG. 1) selected from the following Position 49=L, Position 50=A or W, Position 51=F or N, Position 87=H, and Position 91=T.
 10. The variant of claim 7, wherein the variant comprises an amino acid sequence that is identical to the amino acid sequence of a single variable domain selected from DOM7h-11-12 (SEQ ID NO: 1), DOM7h-11-15 (SEQ ID NO: 2), DOM7h-11-18 (SEQ ID NO: 3) and DOM7h-11-19 (SEQ ID NO: 4) or has up to 4 changes compared to the selected amino acid sequence, provided that the amino acid sequence of the variant has Met at position
 32. 11. The variant of claim 7, wherein the variant comprises an amino acid sequence that is identical to the amino acid sequence of DOM7h-11-15^(S12P) (SEQ ID NO: 414) or has up to 4 changes compared to the selected amino acid sequence, provided that the amino acid sequence of the variant has Met at position
 32. 12. The variant of claim 1, wherein the variant comprises a binding site that specifically binds human SA with a dissociation constant (KD) of from about 0.1 to about 10000 nM, optionally from about 1 to about 6000 nM, as determined by surface plasmon resonance.
 13. The variant of claim 1, wherein the variant comprises a binding site that specifically binds human SA with an off-rate constant (K_(d)) of from about 1.5×10⁻⁴ to about 0.1 sec⁻¹, optionally from about 3×10⁻⁴ to about 0.1 sec⁻¹ as determined by surface plasmon resonance.
 14. The variant of claim 1, wherein the variant comprises a binding site that specifically binds human SA with an on-rate constant (K_(a)) of from about 2×10⁶ to about 1×10⁴M⁻¹sec⁻¹, optionally from about 1×10⁶ to about 2×10⁴M⁻¹sec⁻¹ as determined by surface plasmon resonance.
 15. The variant of claim 1, wherein the variant comprises a binding site that specifically binds Cynomolgus monkey SA with a dissociation constant (KD) of from about 0.1 to about 10000 nM, optionally from about 1 to about 6000 nM, as determined by surface plasmon resonance.
 16. The variant of claim 1, wherein the variant comprises a binding site that specifically binds Cynomolgus monkey SA with an off-rate constant (K_(d)) of from about 1.5×10⁻⁴ to about 0.1 sec⁻¹, optionally from about 3×10⁻⁴ to about 0.1 sec⁻¹ as determined by surface plasmon resonance.
 17. The variant of claim 1, wherein the variant comprises a binding site that specifically binds Cynomolgus monkey SA with an on-rate constant (K_(a)) of from about 2×10⁶ to about 1×10⁴M⁻¹sec⁻¹, optionally from about 1×10⁶ to about 5×10³M⁻¹sec⁻¹ as determined by surface plasmon resonance.
 18. A multispecific ligand comprising an anti-SA variant of claim 1 and a binding moiety that specifically binds a target antigen other than SA.
 19. An anti-SA variant single variable domain of claim 1, wherein the variable domain is conjugated to a drug (optionally an NCE drug), optionally wherein the selected variant is DOM7h-11-15 (SEQ ID NO: 2), DOM7h-11-15^(S12P) (SEQ ID NO: 414) or DOM7h-11-12 (SEQ ID NO: 1).
 20. A fusion protein comprising a polypeptide or peptide drug fused to a variant according to claim 1, optionally wherein the selected variant is DOM7h-11-15 (SEQ ID NO: 2), DOM7h-11-15^(S12P) (SEQ ID NO: 414) or DOM7h-11-12 (SEQ ID NO: 1).
 21. A fusion protein according to claim 20, wherein the fusion protein comprises a linker (eg, a linker comprising the amino acid sequence TVA, optionally TVAAPS) between the variant and the drug.
 22. A composition comprising a variant, fusion protein or ligand of claim 1 and a pharmaceutically acceptable diluent, carrier, excipient or vehicle.
 23. A nucleic acid comprising a nucleotide sequence encoding a variant according to claim
 1. 24. A nucleic acid comprising the nucleotide sequence of a DOM7h-11 variant selected from the nucleotide sequence of DOM7h-11-3 (SEQ ID NO: 5), DOM7h-11-15 (SEQ ID NO: 2), DOM7h-11-12 (SEQ ID NO: 1), DOM7h-11-18 (SEQ ID NO: 3) and DOM7h-11-19 (SEQ ID NO: 4) or a nucleotide sequence that is at least 80% identical to said selected sequence.
 25. A nucleic acid comprising the nucleotide sequence of DOM7h-11-15^(S12P) (SEQ ID NO: 414) or a nucleotide sequence that is at least 80% identical to said selected sequence.
 26. A vector comprising the nucleic acid of claim
 23. 27. An isolated host cell comprising the vector of claim
 26. 28. A method of treating or preventing a disease or disorder in a patient, comprising administering at least one dose of a variant according to claim 1 to said patient. 